Training patients for self‐administration of a new subcutaneous C1‐inhibitor concentrate for hereditary angioedema

Abstract Aims The aim of this study was to provide recommendations for training patients with hereditary angioedema, based on nursing clinical trial experience, to self‐administer subcutaneous C1‐INH (C1‐INH[SC]) used as routine prophylaxis. Background A volume‐reduced, subcutaneous C1‐INH concentrate (C1‐INH(SC); HAEGARDA®; CSL Behring) was recently FDA‐approved for the routine prevention of hereditary angioedema attacks. Nurses will play an important role in patient training. Design Review of a phase 3, randomized, placebo‐controlled, double‐blind, crossover trial of C1‐INH(SC) (COMPACT) and summary of recommendations for training patients based on nurses’ “hands‐on experience.” Methods A panel of nurses with clinical trial experience provided recommendations for patient training. Results Practical suggestions and guidelines were compiled regarding patient selection, product reconstitution and administration and patient follow‐up. Successful patient self‐administration of C1‐INH(SC) can be greatly facilitated by qualified nursing intervention. The information provided in this paper will be useful to nurses anywhere who have an opportunity to interact with patients dealing with hereditary angioedema.

functionality. Clinically, types 1 and 2 are indistinguishable. A third type more recently identified, HAE with normal C1-INH, is much less common and has in some cases been associated with factor XII mutations .
Hereditary angioedema is characterized by recurrent episodes of nonpruritic subcutaneous or submucosal swelling that most commonly affect the extremities, the face, the trunk and abdomen, and the genitals (Bork, Meng, Staubach & Hardt, 2006). The frequency and severity of HAE attacks are generally unpredictable but may be precipitated by triggering events such as physical trauma (e.g., medical and dental procedures), emotional stress and hormonal changes. Untreated attacks can last for hours to days and can be acutely painful, disfiguring, debilitating and life-threatening (Banerji, 2013). Figure 1 contains photos of patients with peripheral and facial HAE attacks. Laryngeal attacks have the potential to cause permanent disability or death and can occur without warning or history of such attacks (Bork, Hardt, & Witzke, 2012). Abdominal attacks with swelling of the intestinal wall are experienced by a majority of patients with HAE; pain, vomiting and diarrhoea associated with these types of attacks can be a significant source of distress and disability and can be misdiagnosed as an acute surgical abdomen process (Bork, Meng, et al., 2006;Bork, Staubach, Eckardt & Hardt, 2006). Considering the chronic, lifelong nature of HAE and the disruptiveness and unpredictability of HAE attacks, it is not surprising that most patients with this disease report a significant impact on their health-related quality of life (HRQOL) . The psychological distress caused by HAE may also potentially contribute to anxiety and depression, as suggested by elevated rates of these disorders in the HAE population Banerji, 2013;Caballero et al., 2014Caballero et al., , 2013Fouche, Saunders, & Craig, 2014;Lumry et al., 2010).

| Background
The goals of HAE management are to reduce morbidity, prevent mortality and improve quality of life to the greatest extent possible. Specific treatment strategies include on-demand treatment of attacks, short-term prophylaxis for anticipated triggers (e.g., surgery, a stressful life event) and/or routine long-term prophylaxis to prevent angioedema attacks (Cicardi et al., 2014Zuraw et al., 2013). It is recommended that all patients with HAE have access to on-demand therapy Lang et al., 2012;Zuraw et al., 2013). HAE-specific medications that are available for the treatment of attacks when they occur include two IV products: C1-INH concentrate (Berinert®; CSL Behring, Marburg, Germany) and recombinant human C1-INH concentrate (Ruconest®; Pharming, Inc., Leiden, the Netherlands) and two subcutaneous (SC) products: the bradykinin B2 receptor antagonist icatibant (Firazyr®, Shire, Lexington, MA, USA) and a kallikrein inhibitor, ecallantide (Kalbitor®, Shire, Lexington, MA, USA).
Routine long-term prevention is considered for patients in whom on-demand acute therapy is inadequate to minimize the personal burden related to HAE Lang et al., 2012;Zuraw et al., 2013). The ideal therapy for this purpose would eliminate attack risk with a high degree of safety and impose minimal burden of its own. Historically, oral attenuated androgens (e.g., danazol, stanozolol) were the primary options for routine prophylaxis in patients with HAE. However, their use is associated with undesirable side effects such as weight gain, acne, headaches in most patients and additionally, virilization and menstrual irregularities in female patients, as well as more serious risks of hepatic adenomas and hepatocellular carcinoma with long-term use (Riedl, 2015;Zuraw, Davis, Castaldo, & Christiansen, 2016 with intravenous (IV) C1-INH concentrate has been shown to reduce HAE attack frequency Zuraw et al., 2010) and improve quality of life in patients (Greeve et al., 2016;Lumry, Miller, Newcomer, Fitts, & Dayno, 2014). The most recent international HAE management guidelines from the World Allergy Organization and the European Academy of Allergy and Clinical Immunology support the use of C1-INH as a first-line option for prophylaxis (Maurer et al., 2018). Recommended dosing is 1,000-2,500 IU given IV every 3-4 days. Patients can be trained to self-administer C1-INH (IV) and this practice has become widely implemented in the US (Riedl, Banerji, & Gower, 2015) and Europe .
Yet, IV self-administration presents particular challenges related to venous access, safety risks of thrombosis and infection from indwelling port use (which some patients prefer to have surgically implanted) and patient convenience issues (Zuraw et al., 2013). In a recent survey of C1-INH(IV) users, more than half reported having problems finding usable veins or other administration problems (Riedl et al., 2017). Further, routine prevention with C1-INH(IV) is not completely effective and many patients continue to experience breakthrough attacks while using it . Ongoing fear of attacks can contribute to higher levels of anxiety and depression in patients with HAE, as has been shown in patients in Europe and the US, even in patients being managed with available medications over recent years (Caballero et al., 2013;Christiansen et al., 2015;Fouche et al., 2014). Full results of the COMPACT study have been published elsewhere . In summary, the mean number of HAE attacks per month was significantly lower during treatment with C1-INH(SC) 60 IU/kg than during treatment with placebo (0.5 vs. 4.0 attacks; within-patient difference, −3.5; p < 0.001); the median reduction in attack rate was 95% and there was a >99% reduction in the use of rescue medications to treat attacks. In addition, the average severity of HAE attacks experienced while on C1-INH(SC) 60 IU/ kg was notably less than during placebo use and no subjects (0%) had a laryngeal attack during the 16 week treatment period with 60 IU/kg C1-INH(SC), whereas nine subjects in this group suffered 12 laryngeal attacks while on placebo. It should be kept in mind that treatment in the COMPACT trial was only 16 weeks and these findings do not guarantee that laryngeal attacks will never occur while In addition, evidence suggests that patients who receive HAE prophylaxis in the home setting may be more adherent to treatment than patients receiving therapy at physicians' offices or infusion centres, possibly because of the added convenience and the reduced travel requirement (Gregory, Landmesser, Corrigan, & Mariano, 2014).

| Subcutaneous C1-INH
International guidelines recommend that all patients with HAE be considered for self-administration if they are willing (Boysen et al., 2013;Longhurst et al., 2010). Appropriate patients for self-administration of HAE medication must be motivated and willing to invest the time and effort necessary to learn self-administration, must be mentally and physically capable of preparing and self-injecting their treatment and should demonstrate reliability (e.g., keeping scheduled appointments) (Shapiro & Zacek, 2014).
Adolescents may be considered for home administration if a responsible adult is willing to undertake training (Longhurst et al., 2010).
Patients of advanced age may also be considered for self-administration if they are willing and able to function safely and effectively, either alone or with a partner. In addition to evaluating the patient's appropriateness for self-administration, it is often the responsibility of the nurse to visit the home to ensure that it provides a safe environment for medication storage and administration (Shapiro & Zacek, 2014).

| Patient education and training
Although some patients may initially be intimidated by the idea of self-administration of SC injections, the provision of appropriate education, training and counselling will allow most patients to feel comfortable with the process (Li, 2016;Shapiro & Zacek, 2014;Symons, Rossi, Magerl, & Andritschke, 2013) and there is a long history of patients with other chronic diseases (e.g., diabetes, primary immune deficiency disease) mastering self-administered SC injec-   Then, carefully remove the clear package from the Mix2Vial transfer set without removing it or touching the exposed end. With the diluent and product vial still attached to the Mix2Vial, gently swirl the product to ensure that the powder is fully dissolved. Do not shake the vial. It can take up to 10 min for the product to dissolve completely.

10
With one hand, grasp the C1-INH(SC) vial and with the other hand grasp the coloured diluent side of the Mix2Vial transfer set and unscrew the set into two pieces.

11
Draw air into an empty, sterile, silicon-free syringe. While the product vial is upright, screw the syringe to the Mix2Vial transfer set. Inject air into the product vial.

12
While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly.

13
Disconnect the filled syringe by unscrewing it from the Mix2Vial transfer set.
14 Visually inspect the final solution. The reconstituted solution should be colourless, clear and free from visible particles. It should not be used if particulate matter or discoloration is observed.

15
The reconstituted solution should be used within 8 hr and stored at room temperature.

16
The filled syringe should be attached to a hypodermic needle or subcutaneous infusion set and the plunger gently pushed to fill the needle or tubing.

17
If the dose requires more than one vial, use a separate, unused Mix2Vial transfer set and diluent vial for each product vial. The needle length should be individualized to adequately reach the subcutaneous layer. In the COMPACT study, patients had a choice between three needle types: a SC injection needle (Hypodermic Pro-Edge), a SC infusion set with a 9 mm needle and a SC infusion set with a 12 mm needle. Approximately one-quarter of patients tried more than one type of needle. There were no apparent trends to suggest an overall preference for any specific needle type. Some patients felt the 12 mm subcutaneous needles were associated with fewer injection site reactions and less leakage compared with shorter needles. For thin patients, 9 mm subcutaneous needles may be adequate and preferred.

TA B L E 2 Injection of C1-INH(SC)
Step Directions Illustration 1 Gently pinch clean skin between thumb and fingers.
2 Remove cap from needle.
• If using a SC infusion set: Bend and hold wings between thumb and index finger.
3 Whether using a SC infusion set or hypodermic syringe, the needle should be inserted under the skin at a 90° or 45° angle.
• The tip of the needle has to pass through the skin layer but not be so deep as to reach the muscle. • Factors such as needle length and thickness of the subcutaneous layer will determine the required angle of injection.

4
If using a SC infusion set, a sterile dressing can be placed over the injection site to secure the needle.

5
The plunger should be pulled back slightly.
• If any blood is observed in the syringe/tubing, the needle and any tubing should be discarded and replaced. • While the syringe with the product can still be used, the injection should be reattempted at a new site.

6
The syringe plunger is slowly pushed to deliver the C1-INH(SC) dose.

7
Rate of injection • Basic rule: Push slowly enough for comfort/tolerability. • An approximate guide for injection rate is about 1 ml/min. • Patients can slow or increase the injection rate according to their comfort level and tolerability.
• If a subcutaneous "bubble" or swelling develops, injection may be too fast and/or too shallow.

8
When infusion is finished, needle is removed and discarded appropriately per local requirements.

9
Patients should be encouraged to record the C1-INH(SC) lot number in a diary or treatment log book.
Note. The information and descriptions provided here are based on clinical trial nurses' experience; for official instructions, please refer to the C1-INH(SC)/HAEGARDA Prescribing Information.

| What to expect from a SC injection of C1-INH(SC)
As with any type of injection, some degree of redness or other local effects are quite normal with the use of C1-INH(SC). As discussed previously, injection site reactions with C1-INH(SC) were common during clinical trials so patients should be prepared for such, yet also reassured that the vast majority of such reactions are mild. all patients being asked. Patients should also understand that some local swelling at the injection site is not uncommon, especially with injected volumes greater than 5-10 ml at a single site.

| Follow-up care
It is critical to keep in close contact with patients during the first few months of C1-INH(SC) use. The frequency of follow-up will depend on the patient, their ability and skill level. Weekly contact for the first month or two may be advisable, with the nature of the contact dictated largely by patient preference (phone, email, SMS text, etc.).
Patients should be encouraged to keep a diary or log book to document their injections and treatment compliance. It is also recommended that patients document and report any breakthrough HAE attacks, their treatment and unusual/lingering symptoms to ensure that all symptoms are being treated appropriately and to help assess the patient's ability to manage their condition (Boysen et al., 2013).
A variety of resources and programs for healthcare providers and patients are available from the manufacturer. These are described on the HAEGARDA product website which includes a tollfree phone number for additional information and support access.

| CON CLUS I ON S AND RELE VAN CE TO CLINI C AL PR AC TI CE
Hereditary angioedema is a burdensome, lifelong disease with significant morbidity and potential mortality. C1-INH(SC) is a safe and effective option for prevention of HAE attacks that offers patients improved disease management. A subcutaneous C1 inhibitor may help overcome many of the challenges associated with IV administration and may provide patients with greater convenience and flexibility in managing their condition. With proper nursing training and support, patients can learn to self-administer C1-INH(SC). A successful transition from the IV to SC formulation can be greatly facilitated F I G U R E 4 Typical mild injection site reaction following a subcutaneous injection by qualified nursing intervention, not to mention patients who have never used injectable medications. The practical information provided in this paper will be useful to nurses anywhere who have an opportunity to interact with patients dealing with HAE.

ACK N OWLED G EM ENTS
The authors would like to recognize the following additional par-