Xolair

Xolair

omalizumab

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Omalizumab.
Description
Each mL of reconstituted Xolair contains omalizumab 125 mg (150 mg in 1.2 mL).
Xolair also contains the following excipients: Powder Vial: Sucrose, L-histidine, L-histidine HCl monohydrate, polysorbate 20. Solvent Ampoule: Water for injections.
Action
Omalizumab, a humanized monoclonal antibody manufactured from a mammalian cell line.
Pharmacology: Pharmacodynamics: Omalizumab is a recombinant DNA-derived humanised monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody is an IgG1-κ that contains human framework regions with the complementary-determining regions of a murine parent antibody that binds to IgE.
Patients with Allergic Asthma: The allergic cascade is initiated when IgE bound to FcεRI (high affinity IgE receptor) receptors on the surface of mast cells and basophils is cross-linked by allergen. This results in the degranulation of these effector cells and the release of histamines, leukotrienes, cytokines and other mediators. These mediators are causally linked to the pathophysiology of allergic asthma including airway oedema, smooth muscle contraction and altered cellular activity associated with the inflammatory process. They also contribute to the signs and symptoms of allergic disease eg, bronchoconstriction, mucus production, wheezing, dyspnoea, chest tightness, nasal congestion, sneezing, itchy, runny nose and itchy, watery eyes.
Omalizumab binds to IgE and prevents binding of IgE to FcεRI, thereby reducing the amount of free IgE that is available to trigger the allergic cascade. Treatment of atopic subjects with omalizumab resulted in a marked down-regulation of FcεRI receptors. Furthermore, the in vitro histamine release from basophils isolated from Xolair-treated subjects was reduced by approximately 90% following stimulation with an allergen compared to pre-treatment values.
In clinical studies in asthma patients, free IgE levels in serum were reduced in a dose-dependent manner within 1 hr following the 1st dose and maintained between doses. Mean decrease in free IgE in serum was >96% using recommended doses. Total IgE levels (ie, bound and unbound) in serum increased after the 1st dose due to the formation of omalizumab: IgE complexes which have a slower elimination rate compared with free IgE. At 16 weeks after the 1st dose, average serum total IgE levels were 5-fold higher compared with pre-treatment levels when using standard assays. After discontinuation of Xolair dosing, the Xolair-induced increase in total IgE and decrease in free IgE were reversible, with no observed rebound in IgE levels after drug washout. Total IgE levels did not return to pre-treatment levels for up to 1 year after discontinuation of Xolair.
Patients with Chronic Spontaneous Urticaria (CSU): There are several theories for the etiology of CSU, including one that suggests an autoimmune origin. Autoimmune antibodies to IgE and its receptor, FcεRI, have been isolated from the serum of some patients with CSU. These autoantibodies can activate basophils or mast cells leading to release of histamine.
One (1) hypothesis for the mechanism of action of omalizumab in CSU is that it lowers free IgE levels in the blood and subsequently in the skin. This leads to down-regulation of surface IgE receptors, thereby decreasing downstream signaling via the FcεRI pathway, resulting in suppressed cell activation and inflammatory responses. As a consequence, the frequency and severity of symptoms of CSU are lessened. Another hypothesis is that lowering circulating free IgE levels leads to a rapid and non-specific desensitization of cutaneous mast cells. Down-regulation of FcεRI may help to sustain the response.
In clinical studies in CSU patients, omalizumab treatment led to a dose-dependent reduction of free IgE and an increase of total IgE levels in serum, similar to the observations in allergic asthma patients. Maximum suppression of free IgE was observed 3 days after the 1st SC dose. After repeated dosing once every 4 weeks, pre-dose serum free IgE levels remained stable between 12 and 24 weeks of treatment. Total IgE levels in serum increased after the 1st dose due to the formation of omalizumab: IgE complexes which have a slower elimination rate compared with free IgE. After repeated dosing once every 4 weeks at 75-300 mg, average predose serum total IgE levels at week 12 were 2- to 3-fold higher compared with pre-treatment levels, and remained stable between 12 and 24 weeks of treatment. After discontinuation of Xolair, free IgE levels increased and total IgE levels decreased towards pre-treatment levels over a 16-week treatment-free follow-up period.
Clinical Experience: Allergic Asthma: Adults and Adolescents >12 years: The safety and efficacy of Xolair were evaluated in 5 randomised, double-blind, placebo-controlled, multicentre trials.
In identical 16-week studies 1 and 2, the safety and efficacy of omalizumab as add-on therapy were demonstrated in 1071 allergic asthmatics, who were symptomatic despite treatment with inhaled corticosteroids (beclomethasone dipropionate 500-1200 mcg/day).
In both trials, omalizumab was superior to placebo with respect to the primary variable of asthma exacerbation (worsening of asthma requiring systemic corticosteroids or a doubling of the patient's baseline beclomethasone dose). The number of asthma exacerbations was significantly lower in the omalizumab group (p=0.006 and p<0.001 in studies 1 and 2, respectively). Fewer omalizumab-treated patients experienced asthma exacerbations (14.6% vs 23.3%, p=0.009 in study 1 and 12.8% vs 30.5%, p<0.001 in study 2).
In double-blind extension phases of both studies up to 1 year, the reduction in the frequency of asthma exacerbations for omalizumab-treated patients compared to placebo-treated patients was maintained.
In studies 1 and 2, clinically meaningful improvement in asthma-related quality of life, measured by the validated Juniper's asthma quality of life questionnaire, was demonstrated in the Xolair group at the end of the 28-week core trial compared to that observed in the placebo-treated group (difference from placebo p≤0.001 in studies 1 and 2).
In study 3, the safety and corticosteroid-sparing effect of omalizumab was demonstrated in 246 patients with severe allergic asthma requiring daily treatment with high-dose inhaled corticosteroids (fluticasone ≥1000 mcg/day) and in whom long-acting β2-agonists were allowed. The study included a 16-week steroid stable phase with study medication added, followed by a 16-week steroid reduction phase. The percent reduction in inhaled corticosteroid dose at the end of the treatment phase was significantly greater in omalizumab-treated patients versus placebo patients (median 60% vs 50%, p=0.003). The proportion of omalizumab patients who were able to reduce their fluticasone dose to ≤500 mcg/day was 60.3% versus 45.8% in the placebo group (p>0.05).
In study 4, the safety and efficacy of omalizumab were demonstrated in 405 patients with co-morbid allergic asthma and perennial allergic rhinitis. Eligible patients had both symptomatic allergic asthma and perennial allergic rhinitis. Patients were treated with omalizumab or placebo for 28 weeks as add-on therapy to ≥400 mcg of budesonide turbuhaler. Inhaled long-acting β2-agonists (39%) and nasal corticosteroids (17%) were allowed.
The co-primary endpoints for study 4 were the incidence of asthma exacerbations (worsening of asthma requiring systemic corticosteroids or a doubling of the patient's baseline budesonide dose) and the proportion of patients in each treatment group with a ≥1 improvement from baseline at the end of the treatment phase in both asthma and rhinitis specific quality of life assessments (Juniper quality of life assessment).
Patients treated with omalizumab had a significantly lower incidence of asthma exacerbations than patients receiving placebo (20.6% omalizumab vs 30.1% placebo, p=0.02) and there was a significantly higher proportion of omalizumab-treated than placebo patients that improved by ≥1 points in both asthma and rhinitis specific quality of life assessments (57.7% omalizumab vs 40.6% placebo, p<0.0001).
The reduction in exacerbations and improvements of quality of life in omalizumab-treated patients were seen in the context of statistically significant improvements in both rhinitis and asthma symptoms, and lung function, compared to placebo.
In study 5, the efficacy and safety of Xolair were demonstrated in a 28-week study involving 419 severe allergic asthmatics, 12-79 years, who had reduced lung function (forced expiratory volume/1 sec: FEV1 40-80% predicted) and poor asthma symptom control despite receiving >1000 mcg of beclomethasone dipropionate (or equivalent) plus long-acting β2-agonist. Eligible patients had experienced multiple asthma exacerbations requiring systemic corticosteroid treatment or had been hospitalised or attended an emergency room due to a severe asthma exacerbation in the past year despite continuous treatment with high-dose inhaled corticosteroids and long-acting β2-agonist. Subcutaneous Xolair or placebo were administered as add-on therapy to >1000 mcg (or equivalent) plus long-acting β2-agonist. Oral corticosteroid (22%), theophylline (27%) and anti-leukotriene (35%) maintenance therapies were allowed. In the treatment phase, concomitant asthma therapy was not changed.
The rate of asthma exacerbations requiring treatment with bursts of systemic corticosteroids was the primary endpoint. Omalizumab reduced the rate of asthma exacerbations by 19% (p=0.153). Further evaluations which did show statistical significance (p<0.05) in favour of Xolair included reductions in severe exacerbations (where patient's lung function was reduced to <60% of personal best and requiring systemic corticosteroids) and asthma-related emergency visits (comprised of hospitalisations, emergency room and unscheduled doctor visits), and improvements in physician's overall assessment of treatment effectiveness, asthma-related quality of life (AQL), asthma symptoms and lung function. A physician's overall assessment was performed in the 5 previously mentioned studies as a broad measure of asthma control performed by the treating physician. The physician was able to take into account peak expiratory flow (PEF), daytime and nighttime symptoms, rescue medication use, spirometry and exacerbations. In all 5 studies, a significantly greater proportion of Xolair-treated patients were judged to have achieved either a marked improvement or complete control of their asthma compared to placebo patients.
Children 6 to <12 years: The primary support for safety and efficacy of Xolair in the 6 to <12 years of age group comes from 1 randomised, double-blind, placebo-controlled, multicentre trial (study 6) and an additional supportive study (study 7).
Study 6 was a 52-week study that evaluated the safety and efficacy of Xolair as add-on therapy in 628 allergic asthmatics who were uncontrolled despite treatment with regular inhaled corticosteroids [fluticasone dry powder inhaler (DPI) ≥200 mcg/day or equivalent] with or without other controller asthma medications. Eligible patients were those with a diagnosis of asthma >1 year and a positive skin prick test to at least 1 perennial aeroallergen and a history of clinical features of moderate to severe persistent asthma including daytime and/or nighttime symptoms along with a history of experiencing exacerbations within the year prior to study entry. Long-acting β2-agonists (67.4%), anti-leukotriene (36.6%) and oral corticosteroid (1.3%) maintenance therapies were allowed. During the first 24 weeks of treatment, a patient's steroid doses remained constant from baseline and this was followed by a 28-week period during which inhaled corticosteroid adjustment was allowed.
A clinically significant exacerbation was defined as a worsening of asthma symptoms as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose for at least 3 days and/or treatment with rescue systemic (oral or IV) corticosteroids for at least 3 days.
Exacerbation rates during the 52-week double-blind treatment period in Xolair patients with FEV1 >80% at baseline had relative decreases of 43% in asthma exacerbations compared with placebo (p<0.001). Xolair patients had statistically significant reduction in the rate of asthma exacerbations irrespective of concomitant long-acting β2-agonist use at baseline compared with placebo patients, representing a 45% decrease for long-acting β2-agonist users and a 42% decrease for long-acting β2-agonist non-users (p<0.001 and p=0.011, respectively).
Study 7 was a 28-week double-blind controlled study primarily evaluating safety in 334 patients who were well controlled with inhaled corticosteroids. During the first 16 weeks, patient's steroid doses remained constant from baseline and this was followed by a 12-week steroid dose reduction period. The study assessed percent reduction in the dose of beclomethasone dipropionate (BDP) and the proportion of patients with a reduction in the dose of BDP at 28 weeks. The percent reduction in the dose of BDP at 28 weeks was higher in the Xolair group than in the placebo group (median reduction 100% vs 66.7%, p=0.001) as well as the proportion of patients with a reduction in the dose of BDP (p=0.002). Frequency and incidence of asthma exacerbation episodes during the steroid dose-reduction phase were also lower in the omalizumab group (mean rate 0.42 vs 0.72, p<0.001; percent patients with exacerbations 18% vs 39%, p<0.001). A trend for superiority of omalizumab with respect to reduction of exacerbation frequency and incidence was evident during the first 16 weeks of the 24-week treatment period. 55.7% omalizumab patients had a complete (100%) reduction in corticosteroid dose at the end of the 28-week treatment period compared with a 43.2% of placebo patients. In addition, more omalizumab patients had a ≥50% reduction in corticosteroid dose compared with placebo (80.4% vs 69.5%, p=0.017).
A physician's overall assessment was performed in the 2 previously mentioned studies (6 and 7) as a broad measure of asthma control performed by the treating physician. The physician was able to take into account PEF, daytime and nighttime symptoms, rescue medication use, spirometry and exacerbations. In both studies a significantly greater proportion of Xolair-treated patients were judged to have achieved either a marked improvement or complete control of their asthma compared to placebo patients.
Chronic Spontaneous Urticaria (CSU): The clinical phase III development program for CSU included 3 randomized, double-blind, placebo controlled, parallel-group, multicenter studies: Q4881g, Q4882g and Q4883g.
Studies Q4881g and Q4882g evaluated efficacy and safety of administration of Xolair 75 mg, 150 mg or 300 mg every 4 weeks for 24 and 12 weeks, respectively, with a 16-week treatment-free follow-up period in patients (12-75 years) with refractory CSU despite H1 antihistamine treatment.
Study Q4883g evaluated safety and efficacy of Xolair 300 mg administered every 4 weeks for 24 weeks, with a 16-week treatment-free follow-up period in patients (12-75 years) with refractory CSU despite H1 and/or H2 antihistamine and/or leukotriene receptor antagonist (LTRA) treatment.
In studies Q4881g and Q4882g the 75 mg dose did not consistently meet either the primary efficacy endpoint (change from baseline to week 12 in weekly itch severity score) or a number of secondary endpoints. It was deemed not efficacious and therefore not further presented.
Change from Baseline to Week 12 in Weekly Itch Severity Score: The primary efficacy endpoint, change from baseline to week 12 in weekly itch severity score was met by both the 150 mg and 300 mg doses in studies Q4881g and Q4882g and by the 300 mg dose in Q4883g. In all 3 studies, the mean weekly itch severity score for both doses increased gradually during the 16-week treatment free follow-up period, consistent with symptom re-occurrence. Mean values at the end of the follow-up period were similar to the placebo group, but lower than respective mean baseline values.
Time to MID Response in Weekly ISS Up To Week 12: In studies Q4881g and Q4882g the median times to attain MID of 5 points on the weekly itch severity score were 2 weeks (p=0.0301 in study Q4881g; p=0.0101 in study Q4882g) for patients in the 150 mg treatment group and 1 week (p<0.0001) for patients in the 300 mg treatment group, compared to 4 weeks for patients in the placebo groups. Similar results were observed in study Q4883g with median time to MID response of 2 weeks in the 300 mg treatment group (p<0.0001) versus 5 weeks in the placebo group.
Change from Baseline to Week 12 in UAS7: In the phase III studies, the omalizumab 150 mg and 300 mg treatment groups showed a statistically significant difference from placebo in mean change from baseline to week 12 in UAS7. Statistical significance (p<0.0001) was achieved in all 3 studies for the 300 mg treatment group, and in studies Q4881g (p=0.0008) and Q4882g (p=0.0001) for the 150 mg treatment group.
Mean UAS7 over time in study Q4881g, displaying a significant decrease from baseline in both treatment groups with a maximum effect around week 12. The magnitude of the effect was maintained during the 24-week treatment period. In studies Q4882g (150 mg and 300 mg over the 12-week treatment period) and Q4883g (300 mg over 24-week treatment period) the results were similar to those of study Q4881g.
In all 3 studies (see Table 2 for study Q4881g), the UAS7 for both omalizumab treatment groups increased gradually during the 16-week treatment-free follow-up period, consistent with symptom reoccurrence. Mean values at the end of the follow-up period were similar to the placebo group but lower than respective mean baseline values.
Proportion of Patients with UAS7 ≤6 at Week 12: The response rates for UAS7 ≤6 at week 12 were all statistically significant, ranging from 52-66% for the 300 mg treatment group (51.9% in Q4881g, 65.8% in Q4882g and 52.4% in Q4883g; p<0.0001) and from 40-43% for the 150 mg treatment group (40% in Q4881g, 42.7% in Q4882g; p<0.001) compared to 11-19% for the placebo group (11.3% in Q4881g, 19% in Q4882g and 12% in Q4883g).
Proportion of Patients with UAS7 (0 at Week 12): The proportion of patients with a complete response, defined by a UAS7=0, was statistically significant for the 300 mg treatment group at week 12, ranging from 34-44% (35.8% in Q4881g, 44.3% in Q4882g, and 33.7% in Q4883g, all p<0.0001) and numerically better for the 150 mg treatment group, with 15% in Q4881g and 22% in Q4882g compared to 5-9% for the placebo group (8.8% in Q4881g, 5.1% in Q4882g and 4.8% in Q4883g).
Changes from Baseline in the Weekly Number of Hives Score at Week 12: In all 3 phase III studies, the mean changes from baseline in the weekly number of hives score at week 12 for the 300 mg treatment groups were statistically significant (p<0.001) displaying a decrease in number of hives score compared to placebo (-11.35 in Q4881g, -11.97 in Q4882g and -10.46 in Q4883g versus -4.37, -5.22 and -4.49 for the corresponding placebo groups). For the 150 mg treatment groups, the mean changes were -7.78 (p=0.0017) in Q4881g and -9.75 (p<0.001) in Q4882g.
Proportion of Angioedema-Free Days From Week 4-12: In all 3 phase III studies, the 300 mg treatment groups consistently achieved the highest mean proportion of angioedema-free days from week 4-12 (96.1% in Q4881g; 95.5% in Q4882g; 91% in Q4883g; all p<0.001) compared to the placebo group (88.2%, 89.2%, 88.1%, respectively). In the 150 mg treatment groups, the mean proportions of angioedema free days for the same time period for studies Q4881g and Q4882g were 89.6% and 91.6%, respectively, with no statistically significant difference to placebo.
Change from Baseline to Week 12 in Overall Dermatology Life Quality Index (DLQI): In all 3 phase III studies, the mean change from baseline to week 12 in the overall DLQI for the 300 mg treatment groups was statistically significantly (p<0.001) greater than placebo showing an improvement of 10.3 points in Q4881g, 10.2 in Q4882g and 9.7 in Q4883g versus 6.1, 6.1 and 5.1 for the corresponding placebo groups. For the 150 mg treatment groups, the mean changes were 8 points (p=0.2286) in Q4881g and 8.3 points (p=0.0215) in Q4882g versus 6.1 for each of the corresponding placebo groups.
Efficacy after 24 weeks of treatment showed similar magnitudes of response as seen at 12 weeks.
Pharmacokinetics: General Characteristics: Absorption: After SC administration, omalizumab is absorbed with an average absolute bioavailability of 62%. The pharmacokinetics of omalizumab are linear at doses >0.5 mg/kg. Administration of Xolair manufactured as a lyophilized or liquid formulation resulted in similar serum concentration-time profiles of omalizumab.
Distribution: In vitro, omalizumab forms complexes of limited size with IgE. Precipitating complexes and complexes larger than 1 million Daltons in molecular weight are not observed in vitro or in vivo.
Tissue distribution studies in cynomolgus monkeys showed no specific uptake of 125I-omalizumab by any organ or tissue.
Elimination: Clearance of omalizumab involves IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG includes degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG is also excreted in bile. In studies with mice and monkeys, omalizumab: IgE complexes were eliminated by interactions with Fcγ receptors within the RES at rates that were generally faster than IgG clearance.
Patients with Allergic Asthma: Absorption: Following a single SC dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7-8 days. Following multiple doses of omalizumab, areas under the serum concentration-time curve from day 0-14 at steady state were up to 6-fold of those after the 1st dose.
Distribution: The apparent volume of distribution of omalizumab in patients with asthma following SC administration was 78±32 mL/kg.
Elimination: In asthma patients omalizumab serum elimination half-life (t½) averaged 26 days, with apparent clearance averaging 2.4±1.1 mL/kg/day. Doubling of body weight approximately doubled apparent clearance.
Age, Race/Ethnicity, Gender, Body Mass Index (BMI): The population pharmacokinetics of Xolair were analyzed to evaluate the effects of demographic characteristics. Analyses of these data suggest that no dose adjustments are necessary in asthma patients for age (6-76 years), race, ethnicity, gender or BMI.
Patients with Chronic Spontaneous Urticaria (CSU): Absorption: Following a single SC dose in adult and adolescent patients with CSU, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 6-8 days. In patients with CSU, omalizumab exhibited linear pharmacokinetics across the dose range of 75-600 mg given as a single SC dose. Following doses of 75 mg, 150 mg or 300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose level.
Distribution: Based on population pharmacokinetic, distribution of omalizumab in CSU patients was similar to that in patients with allergic asthma.
Elimination: In patients with CSU, based on population pharmacokinetic simulations, omalizumab serum elimination (t½) at steady state averaged 24 days and apparent clearance at steady state averaged 240 mL/day (corresponding to 3 mL/kg/day for an 80-kg patient).
Age, Race/Ethnicity, Gender, Body Weight, Body Mass Index, Baseline IgE, Anti-FcεRI Autoantibodies, Co-Medications: The effects of demographic covariates and other factors on omalizumab exposure were evaluated using population pharmacokinetics. In addition, covariate effects were evaluated by analyzing the relationship between omalizumab concentrations and clinical responses. These analyses suggest that no dose adjustments are necessary in patients with CSU for age (12-75 years), race/ethnicity, gender, body weight, body mass index, baseline IgE, anti-FcεRI autoantibodies or concomitant use of H2 antihistamines or leukotriene receptor antagonists (LTRAs).
Patients with Renal and Hepatic Impairment: There are no pharmacokinetic or pharmacodynamic data in patients with renal or hepatic impairment in allergic asthma and CSU patients.
Toxicology: Nonclinical Safety Data: There was no evidence of a systemic anaphylactic response due to mast-cell degranulation in either adult or juvenile cynomolgus monkeys. Circulating omalizumab IgE antibody complexes were present in all monkey studies, however there was no evidence of immune complex-mediated disease in any organ (including the kidney) following omalizumab administration.
Omalizumab: Immunoglobulin E complexes do not fix complement or mediate complement-dependent cytotoxicity.
Chronic administration of omalizumab at dose levels of up to 250 mg/kg was well tolerated in nonhuman primates (both adult and juvenile animals), with the exception of a dose-related decrease in platelet counts that occurred in several nonhuman primate species, at serum concentrations generally in excess of maximum human exposure in pivotal clinical trials. Juvenile monkeys were more sensitive to the platelet effects than adult monkeys. In addition, acute haemorrhage and inflammation were observed at injection sites in cynomolgus monkeys, consistent with a localised immune response to repeated SC administration of a heterologous protein. Formal carcinogenicity studies have not been conducted with omalizumab.
Antibodies to omalizumab were detected in some monkeys following SC or IV administration. This was not unexpected based on administration of a heterologous protein. Some animals could not be evaluated because of high-serum omalizumab concentrations, high IgE levels or both. However, the animals maintained high-serum omalizumab concentrations throughout the treatment periods of the studies, and there was no apparent toxicity due to the presence of anti-omalizumab antibodies.
Indications/Uses
For adults and children (≥6 years) with severe persistent allergic asthma whose symptoms are inadequately controlled with inhaled corticosteroids (ICS) and long-acting β2-agonist (LABA).
For adults and adolescents (≥2 years) with chronic spontaneous urticarial (CSU) refractory to standard of care.
Xolair has been shown to decrease the incidence of asthma exacerbations in these patients. Safety and efficacy have not been established in other allergic conditions.
Dosage/Direction for Use
Allergic Asthma: The appropriate dose and dosing frequency of Xolair is determined by baseline IgE (IU/mL), measured before the start of treatment and body weight (kg). Prior to initial dosing, patients should have their IgE level determined by any commercial serum total IgE assay for their dose assignment. Based on these measurements, Xolair 75-600 mg in 1-4 injections may be needed for each administration. See Table 1 for a conversion chart and Tables 2 and 3 for the dose determination charts in children (6 years to <12 years) and in adults and adolescents (≥12 years). Patients whose baseline IgE levels or body weight (kg) are outside the limits of the dosing table should not be given Xolair.
For SC administration only. Do not administer by the IV or IM route.
Xolair is administered SC every 2 or 4 weeks. Because the solution is slightly viscous, the injection may take 5-10 sec to administer. Doses of >150 mg are divided among >1 injection site to limit injections to not more than 150 mg/site.

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Treatment Duration, Monitoring and Dose Adjustments: In clinical trials, there were reductions in asthma exacerbation events and rescue medication use with improvements in symptom scores during the first 16 weeks of treatment. At least 12 weeks of treatment is required to adequately assess whether or not a patient is responding to Xolair.
Xolair is intended for long-term treatment. Discontinuation generally results in a return to elevated free IgE levels and associated symptoms.
Total IgE levels are elevated during treatment and remain elevated for up to 1 year after the discontinuation of treatment. Therefore, retesting of IgE levels during Xolair treatment cannot be used as a guide for dose determination. Dose determination after treatment interruptions lasting <1 year should be based on serum IgE levels obtained at the initial dose determination. Total serum IgE levels may be retested for dose determination if treatment with Xolair has been interrupted for ≥1 year.
Doses should be adjusted for significant changes in body weight (see Tables 2 and 3).

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Chronic Spontaneous Urticaria (CSU): Recommended Dose: 300 mg by SC injection every 4 weeks. Some patients may achieve control of their symptoms with a dose of 150 mg every 4 weeks.
Overdosage
No case of overdose has been reported. Maximum tolerated dose of Xolair has not been determined. Single IV doses up to 4000 mg have been administered to patients without evidence of dose-limiting toxicities. The highest cumulative dose administered to patients was 44,000 mg over a 20-week period and this dose did not result in any untoward acute effects.
Contraindications
Hypersensitivity to omalizumab or to any of the excipients of Xolair (see Description).
Special Precautions
General: Xolair is not indicated for the treatment of acute asthma exacerbations, acute bronchospasm or status asthmaticus.
Xolair has not been studied in patients with hyperimmunoglobulin E syndrome or allergic bronchopulmonary aspergillosis or for the prevention of anaphylactic reactions.
Xolair has not been adequately studied in atopic dermatitis, allergic rhinitis or food allergy.
Xolair therapy has not been studied in patients with autoimmune diseases, immune complex-mediated conditions, or those with preexisting renal or hepatic impairment. Caution should be exercised when administering Xolair in these patient populations.
Abrupt discontinuation of systemic or inhaled corticosteroids after initiation of Xolair therapy is not recommended. Decreases in corticosteroids should be performed under the direct supervision of a physician and may need to be performed gradually.
Allergic Reactions: As with any protein, local or systemic allergic reactions, including anaphylaxis, may occur when taking omalizumab. Therefore, medications for the treatment of anaphylactic reactions should be available for immediate use following administration of Xolair. Patients should be informed that such reactions are possible and prompt medical attention should be sought if allergic reactions occur. Anaphylactic reactions were rare in clinical trials (see Adverse Reactions). In post-marketing experience, anaphylaxis and anaphylactoid reactions have been reported following the first or subsequent administrations of Xolair. Although most of these reactions occurred within 2 hrs, some occurred >2 hrs.
As with all recombinant DNA-derived humanized monoclonal antibodies, patients may, in rare cases, develop antibodies to omalizumab.
Serum sickness and serum sickness-like reactions, which are delayed allergic type III reactions, have rarely been seen in patients treated with humanized monoclonal antibodies including omalizumab. The onset has typically been 1-5 days after administration of the first or subsequent injections, also after long duration of treatment. Symptoms suggestive of serum sickness include arthritis/arthralgia, rash (urticaria or other forms), fever and lymphadenopathy. Antihistamines and corticosteroids may be useful for preventing or treating this disorder, and patients should be advised to report any suspected symptoms.
Malignancies: During clinical trials for adults and adolescents ≥12 years, there was a numerical imbalance in cancers arising in the Xolair treatment group compared with the control group. The frequency of observed cases was uncommon (<1/100) in both the active and the control group. The overall observed incidence rate of malignancy in the Xolair clinical trial program was comparable to that reported in the general population. There were no cases of malignancy in clinical trials in the 6 to <12 years of age group with omalizumab; there was a single case of malignancy in the control group.
Parasitic Infections: Immunoglobulin E may be involved in the immunological response to some infections. In patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight increase in infection rate with omalizumab, although the course, severity and response to treatment of infection were unaltered. The helminth infection rate in the overall clinical program, which was not designed to detect such infections, was <1 in 1000 patients. However, caution may be warranted in patients at high risk of helminth infection, in particular when traveling to areas where helminthic infections are endemic. If patients do not respond to recommended antihelminth treatment, discontinuation of Xolair should be considered.
Effects on the Ability to Drive or Operate Machinery: Patients receiving Xolair should be informed that dizziness, fatigue, syncope or somnolence may occur in which case, they should avoid driving and using machines.
Use in Pregnancy: There are no adequate and well-controlled studies of omalizumab in pregnant women. Immunoglobulin G molecules are known to cross the placental barrier. Because animal reproduction studies are not always predictive of human response, Xolair should only be used during pregnancy if clearly needed.
Reproduction studies in cynomolgus monkeys have been conducted with omalizumab. Subcutaneous doses up to 75 mg/kg (12-fold the maximum clinical dose) of omalizumab did not elicit maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and did not elicit adverse effects on foetal or neonatal growth when administered throughout late gestation, delivery and nursing.
Although no clinically significant effects on platelets have been observed in patients, doses of omalizumab in excess of the clinical dose have been associated with age-dependent decreases in blood platelets in nonhuman primates, with a greater relative sensitivity in juvenile animals. In reproduction studies in cynomolgus monkeys, there was no clinical evidence of thrombocytopenia in neonatal monkeys from mothers treated with up to 75 mg/kg omalizumab; however, platelet counts were not measured in these offspring.
Use in Lactation: While Xolair presence in human milk has not been studied, IgG is excreted in human milk and therefore, it is expected that Xolair will be present in human milk. The potential for Xolair absorption or harm to the infant are unknown; caution should be exercised when administering Xolair to a nursing woman.
The excretion of omalizumab in milk was evaluated in female cynomolgus monkeys receiving SC doses of 75 mg/kg/week. Neonatal plasma levels of omalizumab after in utero exposure and 28 days of nursing were between 11% and 94% of the maternal plasma level. Milk levels of omalizumab were 1.5% of the maternal blood concentration.
Use in Children: Safety and efficacy in pediatric patients <6 years have not been established and use of Xolair in such patients is therefore not recommended.
Use in the Elderly: There are limited data available on the use of Xolair in patients >65 years but there is no evidence that elderly patients require a different dosage from younger adult patients.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate and well-controlled studies of omalizumab in pregnant women. Immunoglobulin G molecules are known to cross the placental barrier. Because animal reproduction studies are not always predictive of human response, Xolair should only be used during pregnancy if clearly needed.
Reproduction studies in cynomolgus monkeys have been conducted with omalizumab. Subcutaneous doses up to 75 mg/kg (12-fold the maximum clinical dose) of omalizumab did not elicit maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and did not elicit adverse effects on foetal or neonatal growth when administered throughout late gestation, delivery and nursing.
Although no clinically significant effects on platelets have been observed in patients, doses of omalizumab in excess of the clinical dose have been associated with age-dependent decreases in blood platelets in nonhuman primates, with a greater relative sensitivity in juvenile animals. In reproduction studies in cynomolgus monkeys, there was no clinical evidence of thrombocytopenia in neonatal monkeys from mothers treated with up to 75 mg/kg omalizumab; however, platelet counts were not measured in these offspring.
Use in Lactation: While Xolair presence in human milk has not been studied, IgG is excreted in human milk and therefore, it is expected that Xolair will be present in human milk. The potential for Xolair absorption or harm to the infant are unknown; caution should be exercised when administering Xolair to a nursing woman.
The excretion of omalizumab in milk was evaluated in female cynomolgus monkeys receiving SC doses of 75 mg/kg/week. Neonatal plasma levels of omalizumab after in utero exposure and 28 days of nursing were between 11% and 94% of the maternal plasma level. Milk levels of omalizumab were 1.5% of the maternal blood concentration.
Adverse Reactions
During clinical trials with adult and adolescent patients ≥12 years, the most commonly reported adverse reactions were injection site reactions, including injection site pain, swelling, erythema, pruritus and headaches. In clinical trials with patients 6 to <12 years, the most commonly reported adverse reactions were headache, pyrexia and upper abdominal pain. Most of the events were mild or moderate in severity.
The following are adverse reactions recorded in clinical studies in the total safety population treated with Xolair by system organ class and by frequency. Frequencies are defined as: Very common (≥1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (<1/1000).
Infections and Infestations: Uncommon: Pharyngitis. Rare: Parasitic infections.
Immune System Disorders: Rare: Anaphylactic reaction and other allergic conditions, antitherapeutic antibody development.
Nervous System Disorders: Common: Headache*. Uncommon: Dizziness, somnolence, paresthesia, syncope.
Vascular Disorders: Uncommon: Postural hypotension, flushing.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Coughing, allergic bronchospasm. Rare: Laryngoedema.
Gastrointestinal Disorders: Common: Upper abdominal pain**. Uncommon: Nausea, diarrhea, dyspeptic signs and symptoms.
Skin and Subcutaneous Tissue Disorders: Uncommon: Urticaria, rash, pruritus, photosensitivity. Rare: Angioedema.
General Disorders and Administration Site Conditions: Very Common: Pyrexia**. Common: Injection site reactions eg, pain, erythema, pruritus, swelling. Uncommon: Increased weight, fatigue, swelling arms, influenza-like illness.
*Very common in children 6 to <12 years.
**In children 6 to <12 years.
The frequencies of adverse reactions in the active treatment group patients were very similar to those observed in the control group.
Post-Marketing Observations: The following reactions have been identified through spontaneous reporting.
Immune System Disorders (see Precautions): Anaphylaxis and anaphylactoid reactions have been reported following the first or subsequent administrations, serum sickness.
Skin and Subcutaneous Disorders: Alopecia.
Blood and Lymphatic System Disorders: Idiopathic severe thrombocytopenia.
Respiratory, Thoracic and Mediastinal Disorders: Allergic granulomatous angiitis (ie, Churg-Strauss syndrome).
Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia, joint swelling.
Platelets: In clinical trials, few patients experienced platelet counts below the lower limit of the normal laboratory range. None of these changes were associated with bleeding episodes or a decrease in haemoglobin. No pattern of persistent decrease in platelet counts has been reported in humans (patients >6 years), as was observed in nonhuman primates (see Pharmacology: Toxicology under Actions).
Parasitic Infections: See Precautions.
Drug Interactions
Cytochrome P-450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of omalizumab; thus, there is little potential for drug-drug interactions. No formal drug or vaccine interaction studies have been performed with Xolair. There is no pharmacological reason to expect that commonly prescribed medications used in the treatment of asthma or CSU will interact with omalizumab.
Allergic Asthma: In clinical studies, Xolair was commonly used in conjunction with inhaled and oral corticosteroids, inhaled short- and long-acting β2-agonists, leukotriene modifiers, theophyllines and oral antihistamines. There was no indication that the safety of Xolair was altered with these other commonly used asthma medications. Limited data are available on the use of Xolair in combination with specific immunotherapy (hyposensitisation therapy).
Chronic Spontaneous Urticaria (CSU): In clinical studies in CSU, Xolair was used in conjunction with antihistamines (anti-H1, anti-H2) and leukotriene receptor antagonists (LTRAs). There was no evidence that the safety of omalizumab was altered when used with these medicinal products relative to its known safety profile in allergic asthma. In addition, a population pharmacokinetic analysis showed no relevant effect of H2 antihistamines and LTRAs on omalizumab pharmacokinetics.
Incompatibilities: Xolair should not be mixed with any medication or diluents other than sterile water for injections.
Caution For Usage
Instructions for Use and Handling: The lyophilized product takes 15-20 min to dissolve, although in some cases, it may take longer. The fully reconstituted product will appear clear or slightly opaque and may have a few small bubbles or foam around the edge of the vial. Because the reconstituted product is somewhat viscous, care must be taken to withdraw all of the product from the vial before expelling any air or excess solution from the syringe in order to obtain the full 1.2 mL dose.
To prepare Xolair vials for SC administration, adhere to the following instructions:
1. Draw 1.4 mL of water for injections from the ampoule into a syringe equipped with a large-bore 18-gauge needle.
2. With the vial placed upright on a flat surface, insert the needle and transfer the water for injections into the omalizumab vial using standard aseptic techniques, directing the water for injections directly onto the powder.
3. Keeping the vial in an upright position, vigorously swirl the upright vial (do not shake) for approximately 1 min to evenly wet the powder.
4. To aid in dissolution after completing step 3, gently swirl the upright vial for 5-10 sec approximately every 5 min in order to dissolve any remaining solids. (Note that in some cases, it may take >20 min for the powder to dissolve completely. If this is the case, repeat step 4 until there are no visible gel-like particles in the solution.)
When Xolair is fully dissolved, there should be no visible gel-like particles in the solution. It is acceptable to have small bubbles or foam around the edge of the vial. The reconstituted product will appear clear or slightly opaque. Do not use if foreign particles are present.
5. Invert the vial for 15 sec in order to allow the solution to drain towards the stopper. Using a new 3-mL syringe equipped with a large-bore, 18-gauge needle, insert the needle into the inverted vial. Position the needle tip at the very bottom of the solution in the vial stopper when drawing the solution into the syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution from the inverted vial.
6. Replace the 18-gauge needle with a 25-gauge needle for SC injection.
7. Expel air, large bubbles and any excess solution in order to obtain the required 1.2 mL dose. A thin layer of small bubbles may remain at the top of the solution in the syringe. Because the solution is slightly viscous, the injection may take 5-10 sec to administer. The vial delivers 1.2 mL (150 mg) of Xolair.
8. The injections are administered SC in the deltoid region of the arm or the thigh, avoiding urticarial lesions.
Xolair is supplied in a single-use vial and contain no antibacterial preservatives. Chemical and physical stability of the reconstituted product has been demonstrated for 8 hrs at 2-8°C and for 4 hrs at 30°C. From a microbiological point of view, Xolair should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 8 hrs at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Store in a refrigerated condition at 2-8°C. Do not freeze. Xolair can be shipped at controlled ambient temperature (≤30°C) or at 2-8°C.
ATC Classification
R03DX05 - omalizumab ; Belongs to the class of other systemic drugs used in the treatment of obstructive airway diseases.
Presentation/Packing
Powd for inj 150 mg (vial, single-use, lyophilized) x 1's.
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