136 Chapter 7 The bleed rates were reduced substantially before and during the emicizumab therapy and were more reduced in adults/adolescents than in children due to baseline imbalances (as presented in Supplemental Table ST1). Most children (n = 21, 66%) used a local anaesthetic cream (EMLA®) prior to the injection, which has not been reported in existing literature. Except for local pain, there were no documented side effects: no cases of a declining PK profile or suspected ADAs, sudden or gradual loss of response or thrombosis/thrombotic microangiopathy were reported at our center. In several European countries, the drug waste of emicizumab accounted for 6% of its total cost for adolescents/adults and 26% for children . The costs of emicizumab originate from the exorbitant acquisition costs/list pricing costs that are based on separate deals that countries have with the manufacturer, which is why even low drug waste has a considerable financial impact. We demonstrated 9% drug waste in this study, which is in line with previous studies that reported 8.4% for emicizumab and 7–9% for comparable drugs [19, 20]. Furthermore, the 9% drug waste that was observed during this study was calculated based on the manufacturer’s calculator and is probably higher in clinical practice. Especially since the manufacturer prohibits combining two different strengths in one injection syringe, which often leads to a suggestion of at least two injections instead of one injection. As this is very inconvenient for the recipient, the manufacturer’s instructions are probably not adhered to in daily practice, which would implicate that larger vial sizes are used and even more of the drug is wasted, as has been suggested before . Almost all self-reported non-adherent PwHA were teenagers. The injection avoidance might result from a combination of factors, including independence, risky behaviour at that age and painful experiences that might be linked to the high drug viscosity and/or to a lack of adipose tissue in male teenagers. Injection pain seemed an important issue as children had a low BMI and 66% used EMLA prior to injection . The manufacturer’s prohibition to combine two different strengths in one injection syringe, even when the maximum volume for subcutaneous administration (2 mL) is not exceeded, is pointless from a pharmacological perspective and leads to more painful injections per dose, and further reduces the user-friendliness of emicizumab. Fortunately, the forgiveness of poor adherence is higher for emicizumab than for factor replacement therapy due to the drug’s long half-life and the high exposure that comes from label-based dosing. The absence of bleeding on emicizumab might encourage the PwHA to adopt new behaviours that may increase their risk profiles and potentially later lead to more trauma-related bleeds. Treating clinicians should be aware of this potentially changing profile, and inquire about the individual’s pain experience to assist with adequate treatment adherence.