**5. Anti-IgE antibodies in Chronic Spontaneous Urticaria special populations and drug interactions**

To date, ligelizumab have not been investigated pregnant women, children, elderly, history of cancer, patients with renal or hepatic impairment, while only few studies were published regarding the use omalizumab in these special populations.

#### **5.1 Pregnancy**

Currently, omalizumab is not approved for use in pregnancy and there are only few case reports published in literature describing omalizumab as an effective and safe therapy for urticaria in pregnant women [99–102].

The EXPECT study examined 250 women with with moderate-to-severe asthma exposed to omalizumab during pregnancy [102]. Each enrolled patient received at least one dose of omalizumab during pregnancy up to 8 weeks prior to conception. This study compared EXPECT outcomes with those from a disease-matched external population of pregnant women with moderate-to-severe asthma not treated with omalizumab. No significant difference in spontaneous abortions, major congenital anomalies, prematurity, or low birth weight was observed among pregnant women exposed to omalizumab compared with the disease-matched unexposed cohort. However, given the observational nature of this registry, an absence of increased risk with omalizumab cannot be definitively established. Therefore, omalizumab might be considered in pregnant women, but to date its use during pregnancy is not recommended by any accepted international or national guideline. Randomized controlled trials should be conducted on omalizumab during pregnancy before complete reassurance of the drug is established.

#### **5.2 Children**

Randomized controlled trials using omalizumab in urticaria included only a small number of 39 adolescent patients (aged ≥12 years) [103]. Passanisi et al. reported a case series of six children (66.7% males) with a mean age of 14.7 years (range 11–16 years) treated with at least one 6-months course of omalizumab [103]. The average follow-up period was 13 6 months and only one patient was no responder, while three patients needed a second course of treatment. This study demonstrated that omalizumab is effective and safe as treatment option for CSU

unresponsive adolescent patients. Moreover, Passanisi et al. summarized in his study the 12 previously published case reports. Applied omalizumab doses ranged from 75 mg every 4 weeks to 300 mg every 2 weeks for a period of up to 12 months, but most patients received the standard dose of 300 mg every 4 weeks.

Recently, a retrospective multi-center case series reported the use of omalizumab in 19 children (6 to 16.9 years old) with recalcitrant CSU [104]. Sixteen (84%) responded to omalizumab, although two became non-responsive after 6– 12 months of therapy, while three patients (16%) were resistant to treatment, achieving remission through fourth-line (Cyclosporine A) or other therapies. This study stated that children with recalcitrant CSU, even those <12 years old, respond well to standard-dose of omalizumab at rates similar to adults. Future prospective randomized clinical trials of omalizumab and other anti-IgE therapies in children are needed.

#### **5.3 Elderly (65 Years and Older)**

Whilst the randomized clinical trials had an upper age limit of 75 years, the mean age of all included CSU patients was within the range of 40–45 years. Therefore, limited data are now available on the use of anti-IgE antibodies in patients older than 65 years, but there is no evidence that elderly patients require a different dose from younger adult patients. A recent Italian real-life experience on 32 patients ≥65 years of age found that omalizumab is a well-tolerated and effective therapy for elderly patients with nonsedating H1-antihistamine-refractory CSU [105].

### **5.4 History of cancer**

To date, there are only few reports of effective and safe omalizumab treatment in patients with a history of previous cancer (e.g. with breast carcinoma, in-situ melanoma, thyroid carcinoma, laryngeal carcinoma, and pituitary adenoma) [106], while evidence in patients with active malignant disease is scarce. Very rarely CU can be caused by cancer and if so, resolves with its cure [107]. Therefore, current expert opinion suggested that omalizumab can be used in patients with cancer [108].

#### **5.5 Patients with renal or hepatic impairment**

As IgG monoclonal antibodies are mainly eliminated via intracellular catabolism, renal impairment or hepatic impairment is not expected to influence clearance of ligelizumab and omalizumab. No dedicated drug–drug interaction studies have been conducted so far. Hepatic metabolizing enzymes are not involved in monoclonal antibody elimination, consequentely no pharmacokinetic interactions with co-administered medicinal products are expected with the both medications.
