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Indications/Uses
Allergic Asthma: Xolair (omalizumab) is indicated for adults and children (6 years of age and above) with moderate to severe persistent allergic asthma whose symptoms are inadequately controlled with inhaled corticosteroids (ICS).
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.
Nasal Polyps: Xolair (omalizumab) is indicated for adults (18 years of age and above) for the treatment of nasal polyps with inadequate response to intranasal corticosteroids.
Chronic Spontaneous Urticaria (CSU): Xolair (omalizumab) is indicated for adults and adolescents (12 years of age and above) with chronic spontaneous urticaria 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.
Nasal Polyps: Xolair (omalizumab) is indicated for adults (18 years of age and above) for the treatment of nasal polyps with inadequate response to intranasal corticosteroids.
Chronic Spontaneous Urticaria (CSU): Xolair (omalizumab) is indicated for adults and adolescents (12 years of age and above) with chronic spontaneous urticaria refractory to standard of care.
Dosage/Direction for Use
For subcutaneous administration only. Do not administer by the intravenous or intramuscular route.
Dosage for Allergic Asthma: The appropriate dose and dosing frequency of Xolair is determined by baseline immunoglobulin E (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 75 to 600 mg of Xolair in 1 to 4 injections may be needed for each administration. See Tables 4 and 5 for a conversion chart and Tables 6 and 7 for the dose determination charts in children (6 years to less than 12 years of age) and in adults and adolescents (12 years of age and older). For doses of 225, 375 or 525 mg Xolair, 150 mg can be used in combination with Xolair 75 mg.
Patients whose baseline IgE levels or body weight in kilograms are outside the limits of the dosing table should not be given Xolair. (See Tables 4 and Table 5.)
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.
In clinical trials for nasal polyps, changes in nasal polyps score (NPS) and nasal congestion score (NCS) were observed as early as the first assessment at 4 weeks. The need for continued therapy should be periodically reassessed based upon the patient's disease severity and level of symptom control.
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 one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination. Dose determination after treatment interruptions lasting less than one year should be based on serum IgE levels obtained at the initial dose determination. Total serum IgE levels may be re-tested for dose determination if treatment with Xolair has been interrupted for one year or more.
Doses should be adjusted for significant changes in body weight (see Tables 6 and 7).
Dosage for Chronic Spontaneous Urticaria (CSU): The recommended dose is 300 mg by subcutaneous injection every four weeks. Some patients may achieve control of their symptoms with a dose of 150 mg every four weeks.
Special populations: Renal or hepatic impairment: There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of omalizumab. Because omalizumab clearance at clinical doses is dominated by IgG clearance process, including degradation in the reticular endothelial system (RES) it is unlikely to be altered by renal or hepatic impairment. While no particular dose adjustment is recommended, Xolair should be administered with caution in these patients (see PRECAUTIONS).
Pediatric patients: In allergic asthma, safety and efficacy in pediatric patients below the age of 6 have not been established and use of Xolair in such patients is therefore not recommended.
In chronic spontaneous urticaria, safety and efficacy in pediatric patients below the age of 12 years have not been established.
Geriatric patients: There are limited data available on the use of Xolair in patients older than 65 years but there is no evidence that elderly patients require a different dosage from younger adult patients.
Dosage for Allergic Asthma: The appropriate dose and dosing frequency of Xolair is determined by baseline immunoglobulin E (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 75 to 600 mg of Xolair in 1 to 4 injections may be needed for each administration. See Tables 4 and 5 for a conversion chart and Tables 6 and 7 for the dose determination charts in children (6 years to less than 12 years of age) and in adults and adolescents (12 years of age and older). For doses of 225, 375 or 525 mg Xolair, 150 mg can be used in combination with Xolair 75 mg.
Patients whose baseline IgE levels or body weight in kilograms are outside the limits of the dosing table should not be given Xolair. (See Tables 4 and Table 5.)
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.
In clinical trials for nasal polyps, changes in nasal polyps score (NPS) and nasal congestion score (NCS) were observed as early as the first assessment at 4 weeks. The need for continued therapy should be periodically reassessed based upon the patient's disease severity and level of symptom control.
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 one year after the discontinuation of treatment. Therefore, re-testing of IgE levels during Xolair treatment cannot be used as a guide for dose determination. Dose determination after treatment interruptions lasting less than one year should be based on serum IgE levels obtained at the initial dose determination. Total serum IgE levels may be re-tested for dose determination if treatment with Xolair has been interrupted for one year or more.
Doses should be adjusted for significant changes in body weight (see Tables 6 and 7).
Dosage for Chronic Spontaneous Urticaria (CSU): The recommended dose is 300 mg by subcutaneous injection every four weeks. Some patients may achieve control of their symptoms with a dose of 150 mg every four weeks.
Special populations: Renal or hepatic impairment: There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of omalizumab. Because omalizumab clearance at clinical doses is dominated by IgG clearance process, including degradation in the reticular endothelial system (RES) it is unlikely to be altered by renal or hepatic impairment. While no particular dose adjustment is recommended, Xolair should be administered with caution in these patients (see PRECAUTIONS).
Pediatric patients: In allergic asthma, safety and efficacy in pediatric patients below the age of 6 have not been established and use of Xolair in such patients is therefore not recommended.
In chronic spontaneous urticaria, safety and efficacy in pediatric patients below the age of 12 years have not been established.
Geriatric patients: There are limited data available on the use of Xolair in patients older than 65 years but there is no evidence that elderly patients require a different dosage from younger adult patients.
Overdosage
No case of overdose has been reported. Maximum tolerated dose of Xolair has not been determined. Single intravenous doses up to 4,000 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 the active substance or to any of the excipients (see Description).
Special Precautions
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. Most of these reactions occurred within 2 hours. As with all recombinant DNA derived humanized monoclonal antibodies patients may in rare cases develop antibodies to omalizumab (see ADVERSE REACTIONS).
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.
Parasitic infections: IgE may be involved in the immunological response to some infections. In patients at chronic high risk of helminth infection, a placebo-controlled trial in allergic patients 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 less than 1 in 1,000 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 anti-helminth treatment, discontinuation of Xolair should be considered.
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 pre-existing 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.
Advice to handler: For subcutaneous administration only. Do not administer by the intravenous or intramuscular route.
Pre-filled syringe, latex-sensitive individuals: The removable needle cap of Xolair solution for injection in pre-filled syringe contains a derivative of natural rubber latex. Although no natural rubber latex is detected in the removable needle cap, the safe use of Xolair solution for injection in pre-filled syringe in latex-sensitive individuals has not been studied.
In post-marketing experience, anaphylaxis and anaphylactoid reactions have been reported following the first or subsequent administrations of Xolair. Most of these reactions occurred within 2 hours. As with all recombinant DNA derived humanized monoclonal antibodies patients may in rare cases develop antibodies to omalizumab (see ADVERSE REACTIONS).
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.
Parasitic infections: IgE may be involved in the immunological response to some infections. In patients at chronic high risk of helminth infection, a placebo-controlled trial in allergic patients 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 less than 1 in 1,000 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 anti-helminth treatment, discontinuation of Xolair should be considered.
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 pre-existing 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.
Advice to handler: For subcutaneous administration only. Do not administer by the intravenous or intramuscular route.
Pre-filled syringe, latex-sensitive individuals: The removable needle cap of Xolair solution for injection in pre-filled syringe contains a derivative of natural rubber latex. Although no natural rubber latex is detected in the removable needle cap, the safe use of Xolair solution for injection in pre-filled syringe in latex-sensitive individuals has not been studied.
Use In Pregnancy & Lactation
Women of Child-bearing potential: There are no special recommendations for women of child-bearing potential.
Pregnancy: There are no adequate and well-controlled studies of omalizumab in pregnant women. IgG 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 per week (at least 8-fold the highest recommended clinical dose in mg/kg over a 4-week period) of omalizumab did not elicit maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and did not elicit adverse effects on fetal 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.
Breast-feeding: While omalizumab presence in human milk has not been studied, IgG is excreted in human milk and therefore it is expected that omalizumab will be present in human milk. The potential for omalizumab 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 subcutaneous doses of 75 mg/kg/week. Neonatal serum levels of omalizumab after in utero exposure and 28 days of nursing were between 11% and 94% of the maternal serum level. Milk levels of omalizumab were 0.15% of the maternal serum concentration.
Fertility: There are no human fertility data for omalizumab. In specifically-designed non clinical fertility studies in adult cynomolgus monkeys, including mating studies, no impairment of male or female fertility was observed following repeated dosing with omalizumab at dose levels up to 75 mg/kg.
Pregnancy: There are no adequate and well-controlled studies of omalizumab in pregnant women. IgG 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 per week (at least 8-fold the highest recommended clinical dose in mg/kg over a 4-week period) of omalizumab did not elicit maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and did not elicit adverse effects on fetal 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.
Breast-feeding: While omalizumab presence in human milk has not been studied, IgG is excreted in human milk and therefore it is expected that omalizumab will be present in human milk. The potential for omalizumab 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 subcutaneous doses of 75 mg/kg/week. Neonatal serum levels of omalizumab after in utero exposure and 28 days of nursing were between 11% and 94% of the maternal serum level. Milk levels of omalizumab were 0.15% of the maternal serum concentration.
Fertility: There are no human fertility data for omalizumab. In specifically-designed non clinical fertility studies in adult cynomolgus monkeys, including mating studies, no impairment of male or female fertility was observed following repeated dosing with omalizumab at dose levels up to 75 mg/kg.
Adverse Reactions
Allergic Asthma: Summary of the safety profile: During clinical studies with adult and adolescent patients 12 years of age and older, the most commonly reported adverse reactions were headaches and injection site reactions, including injection site pain, swelling, erythema and pruritus. In clinical studies with patients 6 to <12 years of age, the most commonly reported adverse reactions were headache, pyrexia and upper abdominal pain. Most of the events were mild or moderate in severity.
Tabulated summary of adverse reactions from the clinical studies: Table 8 lists the adverse reactions recorded in clinical studies in the total allergic asthma safety population treated with Xolair by system organ class and by frequency. Frequencies are defined as: Very common (≥1/10), common (>1/100; <1/10), uncommon (>1/1000; <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000). (See Table 8.)
The frequencies of adverse reactions in the active treatment group patients were very similar to those observed in the control group.
Listing of adverse drug reactions from post-marketing spontaneous reports: 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 (i.e. Churg Strauss syndrome).
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, joint swelling.
Chronic Spontaneous Urticaria (CSU): Summary of the safety profile: The safety and tolerability of omalizumab were investigated with the doses of 75 mg, 150 mg and 300 mg every four weeks in 975 CSU patients, 242 of whom received placebo. 733 patients were treated with omalizumab for up to 12 weeks and 490 patients for up to 24 weeks. 175 and 412 patients were treated for up to 12 weeks and 87 and 333 patients were treated for up to 24 weeks at the recommended doses of 150 mg and 300 mg respectively.
Tabulated summary of adverse reactions from the clinical studies at the recommended doses (150 mg and 300 mg): Adverse reactions (events occurring in ≥1% of patients in any treatment group and ≥2% more frequently in any omalizumab treatment group than in the placebo group after medical review) reported at the recommended doses (150 mg and 300 mg) in the three pooled Phase III studies are listed by MedDRA system organ class (Table 9). Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions listed first. The corresponding frequency category for each adverse reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See Table 9.)
Additional events reported anytime during the day 1 to week 24 treatment period (studies Q4881g and Q4883g) that met the criteria of adverse reactions: Infections and infestations: upper respiratory tract infections (placebo 3.1%, 150 mg 3.4%, 300 mg 5.7%), urinary tract infection (placebo 1.8%, 150 mg 4.6%, 300 mg 2.4%).
Nervous system disorders: sinus headache (placebo 0%, 150 mg 2.3%, 300 mg 0.3%).
Musculoskeletal and connective tissue disorders: myalgia (placebo 0%, 150 mg 2.3%, 300 mg 0.9%), pain in extremity (placebo 0%, 150 mg 3.4%, 300 mg 0.9%), musculoskeletal pain (placebo 0%, 150 mg 2.3%, 300 mg 0.9%).
General disorders and administration site conditions: pyrexia (placebo 1.2%, 150 mg 3.4%, 300 mg 0.9%).
Injection site reactions: Injection site reactions occurred during the studies in more omalizumab-treated patients than placebo patients (2.7% at 300 mg, 0.6% at 150 mg, 0.8% with placebo). They included: swelling, erythema, pain, bruising, itching, bleeding and urticaria.
Description of safety aspects of special interest pertinent to allergic asthma and CSU indications: No relevant data was obtained in clinical studies in CSU that would require a modification of the sections as follows.
Anaphylaxis: In post-marketing reports, the frequency of anaphylaxis in patients exposed to Xolair use was estimated to be 0.2% based on a total number of anaphylactic reactions observed from an estimated exposure of over 500,000 patient years.
A history of anaphylaxis unrelated to omalizumab may be a risk factor for anaphylaxis following Xolair administration.
Malignancies: During initial clinical trials in adults and adolescents 12 years of age and older, there was a numerical imbalance in cancers arising in the active treatment group, compared with the control group. The number of observed cases was uncommon (<1/100) in both the active and the control group. In a subsequent observational study comparing 5,007 Xolair-treated and 2,829 non-Xolair-treated patients followed for up to 5 years, the incidence rates of primary malignancies per 1,000 patient years were 16.01 (295/18,426 patient years) and 19.07 (190/9,963 patients years), respectively, which does not indicate an increased malignancy risk (rate ratio 0.84, 95% confidence interval, 0.62 to 1.13). In a further analysis of randomized, double-blind, placebo-controlled clinical trials including 4,254 patients on Xolair and 3,178 patients on placebo, Xolair treatment was not associated with an increased malignancy risk based on incidence rates per 1,000 patient years of 4.14 (14/3,382 patient years) for Xolair treated patients and 4.45 (11/2,474 patient years) for placebo patients (rate ratio 0.93, 95% confidence interval 0.39 to 2.27). 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.
Arterial Thromboembolic Events (ATE): In controlled clinical trials and during interim analyses of an observational study, a numerical imbalance of ATEs was observed. ATE included stroke, transient ischemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause). In the final analysis of the observational study, the rate of ATE per 1,000 patient years was 7.52 (115/15,286 patients years) for Xolair-treated patients and 5.12 (51/9,963 patient years) for control patients. In a multivariate analysis controlling for available baseline cardiovascular risk factors, the hazard ratio was 1.32 (95% confidence interval 0.91 to 1.91). In a separate analysis of pooled clinical trials including all randomized double-blind, placebo-controlled clinical trials of 8 or more weeks duration, the rate of ATE per 1000 patient years was 2.69 (5/1,856 patients years) for Xolair-treated patients and 2.38 (4/1,680 patient years) for placebo patients (rate ratio 1.13, 95% confidence interval 0.24 to 5.71).
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 hemoglobin. No pattern of persistent decrease in platelet counts has been reported in humans (patients greater than 6 years of age), as was observed in non-human primates (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Parasitic infections: In allergic patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight numerical increase in infection rate with omalizumab that was not statistically significant. The course, severity, and response to treatment of infections were unaltered (see PRECAUTIONS).
Tabulated summary of adverse reactions from the clinical studies: Table 8 lists the adverse reactions recorded in clinical studies in the total allergic asthma safety population treated with Xolair by system organ class and by frequency. Frequencies are defined as: Very common (≥1/10), common (>1/100; <1/10), uncommon (>1/1000; <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000). (See Table 8.)
The frequencies of adverse reactions in the active treatment group patients were very similar to those observed in the control group.
Listing of adverse drug reactions from post-marketing spontaneous reports: 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 (i.e. Churg Strauss syndrome).
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, joint swelling.
Chronic Spontaneous Urticaria (CSU): Summary of the safety profile: The safety and tolerability of omalizumab were investigated with the doses of 75 mg, 150 mg and 300 mg every four weeks in 975 CSU patients, 242 of whom received placebo. 733 patients were treated with omalizumab for up to 12 weeks and 490 patients for up to 24 weeks. 175 and 412 patients were treated for up to 12 weeks and 87 and 333 patients were treated for up to 24 weeks at the recommended doses of 150 mg and 300 mg respectively.
Tabulated summary of adverse reactions from the clinical studies at the recommended doses (150 mg and 300 mg): Adverse reactions (events occurring in ≥1% of patients in any treatment group and ≥2% more frequently in any omalizumab treatment group than in the placebo group after medical review) reported at the recommended doses (150 mg and 300 mg) in the three pooled Phase III studies are listed by MedDRA system organ class (Table 9). Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions listed first. The corresponding frequency category for each adverse reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See Table 9.)
Additional events reported anytime during the day 1 to week 24 treatment period (studies Q4881g and Q4883g) that met the criteria of adverse reactions: Infections and infestations: upper respiratory tract infections (placebo 3.1%, 150 mg 3.4%, 300 mg 5.7%), urinary tract infection (placebo 1.8%, 150 mg 4.6%, 300 mg 2.4%).
Nervous system disorders: sinus headache (placebo 0%, 150 mg 2.3%, 300 mg 0.3%).
Musculoskeletal and connective tissue disorders: myalgia (placebo 0%, 150 mg 2.3%, 300 mg 0.9%), pain in extremity (placebo 0%, 150 mg 3.4%, 300 mg 0.9%), musculoskeletal pain (placebo 0%, 150 mg 2.3%, 300 mg 0.9%).
General disorders and administration site conditions: pyrexia (placebo 1.2%, 150 mg 3.4%, 300 mg 0.9%).
Injection site reactions: Injection site reactions occurred during the studies in more omalizumab-treated patients than placebo patients (2.7% at 300 mg, 0.6% at 150 mg, 0.8% with placebo). They included: swelling, erythema, pain, bruising, itching, bleeding and urticaria.
Description of safety aspects of special interest pertinent to allergic asthma and CSU indications: No relevant data was obtained in clinical studies in CSU that would require a modification of the sections as follows.
Anaphylaxis: In post-marketing reports, the frequency of anaphylaxis in patients exposed to Xolair use was estimated to be 0.2% based on a total number of anaphylactic reactions observed from an estimated exposure of over 500,000 patient years.
A history of anaphylaxis unrelated to omalizumab may be a risk factor for anaphylaxis following Xolair administration.
Malignancies: During initial clinical trials in adults and adolescents 12 years of age and older, there was a numerical imbalance in cancers arising in the active treatment group, compared with the control group. The number of observed cases was uncommon (<1/100) in both the active and the control group. In a subsequent observational study comparing 5,007 Xolair-treated and 2,829 non-Xolair-treated patients followed for up to 5 years, the incidence rates of primary malignancies per 1,000 patient years were 16.01 (295/18,426 patient years) and 19.07 (190/9,963 patients years), respectively, which does not indicate an increased malignancy risk (rate ratio 0.84, 95% confidence interval, 0.62 to 1.13). In a further analysis of randomized, double-blind, placebo-controlled clinical trials including 4,254 patients on Xolair and 3,178 patients on placebo, Xolair treatment was not associated with an increased malignancy risk based on incidence rates per 1,000 patient years of 4.14 (14/3,382 patient years) for Xolair treated patients and 4.45 (11/2,474 patient years) for placebo patients (rate ratio 0.93, 95% confidence interval 0.39 to 2.27). 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.
Arterial Thromboembolic Events (ATE): In controlled clinical trials and during interim analyses of an observational study, a numerical imbalance of ATEs was observed. ATE included stroke, transient ischemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause). In the final analysis of the observational study, the rate of ATE per 1,000 patient years was 7.52 (115/15,286 patients years) for Xolair-treated patients and 5.12 (51/9,963 patient years) for control patients. In a multivariate analysis controlling for available baseline cardiovascular risk factors, the hazard ratio was 1.32 (95% confidence interval 0.91 to 1.91). In a separate analysis of pooled clinical trials including all randomized double-blind, placebo-controlled clinical trials of 8 or more weeks duration, the rate of ATE per 1000 patient years was 2.69 (5/1,856 patients years) for Xolair-treated patients and 2.38 (4/1,680 patient years) for placebo patients (rate ratio 1.13, 95% confidence interval 0.24 to 5.71).
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 hemoglobin. No pattern of persistent decrease in platelet counts has been reported in humans (patients greater than 6 years of age), as was observed in non-human primates (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Parasitic infections: In allergic patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight numerical increase in infection rate with omalizumab that was not statistically significant. The course, severity, and response to treatment of infections were unaltered (see PRECAUTIONS).
Caution For Usage
Incompatibilities: Powder and solvent for solution for injection: Xolair should not be mixed with any medication or diluents other than sterile water for injection.
Instructions For Use and Handling: Xolair powder vial and solvent for solution for injection: Xolair 75 mg and 150 mg powder for solution for injection are supplied in a single-use vial and contain no antibacterial preservatives. Chemical and physical stability of the reconstituted product has been demonstrated for 8 hours at 2°C to 8°C and for 4 hours at 30°C. From a microbiological point of view, the product 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 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
The lyophilized product takes 15-20 minutes to dissolve, although in some cases it may take longer. The fully reconstituted product will appear clear to slightly opalescent, colorless to pale brownish-yellow 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 0.6 mL or 1.2 mL dose.
To prepare Xolair for subcutaneous administration, please adhere to the following instructions: For Xolair 150 mg vials: 1. Draw 1.4 mL of water for injection 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 minute to evenly wet the powder.
4. To aid in dissolution after completing step 3, gently swirl the upright vial for 5-10 seconds approximately every 5 minutes in order to dissolve any remaining solids.
* Note that in some cases it may take longer than 20 minutes 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 the product 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 seconds in order to allow the solution to drain towards the stopper. Using a new 3-cc 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 subcutaneous 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 seconds to administer. The vial delivers 1.2 mL (150 mg) of Xolair.
8. The injections are administered subcutaneously in the deltoid region of the arm or the thigh, avoiding urticarial lesions.
Special precautions for disposal: Xolair powder vial and solvent for solution for injection: Any unused product or waste material should be disposed of in accordance with local requirements.
Instructions For Use and Handling: Xolair powder vial and solvent for solution for injection: Xolair 75 mg and 150 mg powder for solution for injection are supplied in a single-use vial and contain no antibacterial preservatives. Chemical and physical stability of the reconstituted product has been demonstrated for 8 hours at 2°C to 8°C and for 4 hours at 30°C. From a microbiological point of view, the product 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 hours at 2°C to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.
The lyophilized product takes 15-20 minutes to dissolve, although in some cases it may take longer. The fully reconstituted product will appear clear to slightly opalescent, colorless to pale brownish-yellow 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 0.6 mL or 1.2 mL dose.
To prepare Xolair for subcutaneous administration, please adhere to the following instructions: For Xolair 150 mg vials: 1. Draw 1.4 mL of water for injection 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 minute to evenly wet the powder.
4. To aid in dissolution after completing step 3, gently swirl the upright vial for 5-10 seconds approximately every 5 minutes in order to dissolve any remaining solids.
* Note that in some cases it may take longer than 20 minutes 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 the product 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 seconds in order to allow the solution to drain towards the stopper. Using a new 3-cc 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 subcutaneous 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 seconds to administer. The vial delivers 1.2 mL (150 mg) of Xolair.
8. The injections are administered subcutaneously in the deltoid region of the arm or the thigh, avoiding urticarial lesions.
Special precautions for disposal: Xolair powder vial and solvent for solution for injection: Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Xolair must be stored in a refrigerated condition at 2°C-8°C. Do not freeze. In order to protect from light, store in the original package.
The shelf life includes potential temperature excursions.
The shelf life includes potential temperature excursions.
Action
Pharmacology: Pharmacodynamics: General characteristics: Omalizumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody is an IgG1 kappa 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 the high affinity IgE receptor, FcεRI, 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 edema, smooth muscle contraction and altered cellular activity associated with the inflammatory process. They also contribute to the signs and symptoms of allergic disease such as bronchoconstriction, mucus production, wheezing, dyspnea, 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 one hour following the first dose and maintained between doses. Mean decrease in free IgE in serum was greater than 96% using recommended doses. Total IgE levels (i.e., bound and unbound) in serum increased after the first dose due to the formation of omalizumab: IgE complexes which have a slower elimination rate compared with free IgE. At 16 weeks after the first dose, average serum total IgE levels were five-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 one 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 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 first subcutaneous 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 first 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 mg to 300 mg, average predose serum total IgE levels at week 12 were two-to three-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 Studies: Allergic Asthma: Adults and adolescents >12 years of age: The safety and efficacy of Xolair were evaluated in five randomized, double-blind, placebo controlled, multi-center trials.
In identical 16-week studies 1 and 2, the safety and efficacy of omalizumab as add-on therapy were demonstrated in 1,071 allergic asthmatics, who were symptomatic despite treatment with inhaled corticosteroids (beclomethasone dipropionate 500 to 1,200 micrograms/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 out to one 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 ≥1,000 micrograms/day) and in whom long-acting beta2-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 micrograms/day was 60.3% versus 45.8% in the placebo group.
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 micrograms of Budesonide Turbohaler. Inhaled long-acting beta2-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 ≥1.0 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 ≥1.0 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, ages 12 to 79 years, who had reduced lung function (Forced Expiratory Volume/1 second: FEV1 40 to 80% predicted) and poor asthma symptom control despite receiving >1,000 micrograms of beclomethasone dipropionate (or equivalent) plus long-acting beta2-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 beta2-agonist. Subcutaneous Xolair or placebo were administered as add-on therapy to >1,000 micrograms beclomethasone dipropionate (or equivalent) plus long-acting beta2-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 below 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 five above 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), day and night time symptoms, rescue medication use, spirometry and exacerbations. In all five 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 of age: The primary support for safety and efficacy of Xolair in the 6 to <12 years of age group comes from one randomized, double-blind, placebo controlled, multi-center 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 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 one perennial aeroallergen and a history of clinical features of moderate to severe persistent asthma including daytime and/or night-time symptoms along with a history of experiencing exacerbations within the year prior to study entry. Long-acting beta2-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 I.V. (intravenous)) 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 beta2-agonist use at baseline compared with placebo patients, representing a 45% decrease for long-acting beta2-agonist users and a 42% decrease for long-acting beta2-agonist non-users (p<0.001 and p=0.011, respectively).
Study 7 was a 28 week randomized, double blind, placebo-controlled study primarily evaluating safety in 334 children, aged 6-12 years of age, with asthma who were well controlled with inhaled corticosteroids. During the first 16 weeks of treatment, patients' 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 two above 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, day and night time 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 three randomized, double-blind, placebo controlled, parallel-group, multi-center studies: Q4881g, Q4882g and Q4883g.
Studies Q4881g and Q4882g evaluated efficacy and safety of administration of 75 mg, 150 mg, or 300 mg Xolair every 4 weeks for 24 and 12 weeks respectively, with a 16-week treatment-free follow-up period in patients (12 to 75 years) with refractory CSU despite H1 antihistamine treatment.
Study Q4883g evaluated safety and efficacy of 300 mg Xolair administered every 4 weeks for 24 weeks, with a 16-week treatment-free follow-up period in patients (12 to 75 years) with refractory CSU despite H1 and/or H2 antihistamine and/or leukotriene receptor antagonist (LTRA) treatment. (See Table 1.)
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 (secondary endpoint: see Table 2).
Figure 1 shows the mean weekly itch severity score over time in study Q4881g. The mean weekly itch severity scores significantly decreased in both treatment groups with a maximum effect around week 12 that was sustained over the 24-week treatment period. In studies Q4883g (300 mg over the 24-week treatment period) and Q4882g (150 mg and 300 mg over the 12-week treatment period) the results were similar to those of study Q4881g.
In all three studies (see Figure 1 for study Q4881g), 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. (See Figure 1.)
Time to Minimal Important Difference (MID) response of 5 points in weekly ISS up to week 12: In studies Q4881g and Q4882g the times to attain MID of 5 points on the weekly itch severity score were statistically significantly shorter for patients in the 300 mg treatment groups, compared to the placebo groups with p-value <0.0001. A shorter time was also observed for the 150 mg treatment groups compared to placebo with p=0.0301 in study Q4881g and p=0.0101 in study Q4882g. The median times for attaining MID response were 1 week in the 300 mg treatment group, 2 weeks in the 150 mg groups and 4 weeks for placebo.
Similar results were observed in study Q4883g with p<0.0001 (median time to MID response was 2 weeks in the 300 mg treatment group and 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 (Figure 2 for study Q4881g). Statistical significance (p<0.0001) was achieved in all three 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.
Figure 2 shows 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 three studies (see Figure 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 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. (See Figure 2.)
Proportion of patients with UAS7 ≤ 6 at week 12: The proportions of patients with a UAS7 ≤6 at week 12 are shown in Figure 3. The response rates ranged from 52-66% (300 mg dose), all were statistically significantly higher compared to 11-19% in the placebo group (p<0.0001). The response rates for the 150 mg dose show a notable difference (40-43%; p≤0.001) compared to placebo. (See Figure 3.)
Proportion of patients with UAS7 = 0 at week 12: The proportion of patients with a complete response shown by a UAS7 = 0 at week 12 ranged from 34 to 44% (300 mg dose, statistically significant, all p<0.0001) compared to 5 to 9% in the placebo groups. In the 150 mg treatment groups, a clinically notable difference compared to placebo was observed ranging from 15 to 22% (Figure 4). (See Figure 4.)
Changes from baseline in the weekly number of hives score at week 12: In all three phase III studies, the difference from placebo in mean changes from baseline in the weekly number of hives score at week 12 for the 300 mg treatment groups was statistically significant 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; all p<0.0001). 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 to week 12: In all three Phase III studies the 300 mg treatment groups consistently achieved the highest mean proportion of angioedema-free days from week 4 to week 12 (91 to 96%). The increase in the proportion of angioedema-free days compared to placebo was statistically significant (p<0.001) (Fig 5). In the 150 mg treatment group, the mean proportions of angioedema-free days for the same time period for studies Q4881g and Q4882g were 89.6% and 91.6% respectively. The corresponding placebo values for the same studies were 88.2% and 89.2%. In both of these studies, the differences from placebo did not achieve statistical significance for the 150 mg dose. (See Figure 5.)
Change from baseline to week 12 in overall Dermatology Life Quality Index (DLQI): In all three Phase III studies, the change from baseline to week 12 in the overall DLQI for the 300 mg treatment group was statistically significantly (p<0.001) greater compared to placebo. The 150 mg omalizumab group showed a clinically notable difference to placebo in study Q4882g (Figure 6). (See Figure 6.)
Efficacy after 24 weeks of treatment: Table 3 shows the results after 24 weeks of treatment. Similar magnitudes of response are seen as at 12 weeks. (See Table 3.)
Pharmacokinetics: General characteristics: Absorption: After subcutaneous administration, omalizumab is absorbed with an average absolute bioavailability of 62%. The pharmacokinetics of omalizumab are linear at doses greater than 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 one 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 subcutaneous dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7 to 8 days. Following multiple doses of omalizumab, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose.
Distribution: The apparent volume of distribution of omalizumab in patients with asthma following subcutaneous administration was 78 ± 32 mL/kg.
Elimination: In asthma patients omalizumab serum elimination half-life 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: The population pharmacokinetics of omalizumab 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 to 76 years), race, ethnicity, gender or body mass index.
Patients with Chronic Spontaneous Urticaria (CSU): Absorption: Following a single subcutaneous dose in adult and adolescent patients with CSU, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 6 to 8 days.
In patients with CSU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as a single subcutaneous 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 half-life at steady state averaged 24 days and apparent clearance at steady state averaged 240 mL/day (corresponding to 3.0 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 to 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 (see PRECAUTIONS).
Toxicology: Non-clinical 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: IgE complexes do not fix complement or mediate complement-dependent cytotoxicity.
Chronic administration of omalizumab at dose levels of up to 250 mg/kg (at least 14-fold the highest recommended clinical dose in mg/kg) was well tolerated in non-human primates (both adult and juvenile animals), with the exception of a dose-related decrease in platelet counts that occurred in several non-human 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 hemorrhage and inflammation were observed at injection sites in cynomolgus monkeys, consistent with a localized immune response to repeated subcutaneous administration of a heterologous protein. Formal carcinogenicity studies have not been conducted with omalizumab.
Antibodies to omalizumab were detected in some monkeys following subcutaneous or intravenous 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.
Reproduction, milk excretion and fertility studies in animals are described in USE IN PREGNANCY & LACTATION.
Patients with Allergic Asthma: The allergic cascade is initiated when IgE bound to the high affinity IgE receptor, FcεRI, 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 edema, smooth muscle contraction and altered cellular activity associated with the inflammatory process. They also contribute to the signs and symptoms of allergic disease such as bronchoconstriction, mucus production, wheezing, dyspnea, 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 one hour following the first dose and maintained between doses. Mean decrease in free IgE in serum was greater than 96% using recommended doses. Total IgE levels (i.e., bound and unbound) in serum increased after the first dose due to the formation of omalizumab: IgE complexes which have a slower elimination rate compared with free IgE. At 16 weeks after the first dose, average serum total IgE levels were five-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 one 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 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 first subcutaneous 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 first 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 mg to 300 mg, average predose serum total IgE levels at week 12 were two-to three-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 Studies: Allergic Asthma: Adults and adolescents >12 years of age: The safety and efficacy of Xolair were evaluated in five randomized, double-blind, placebo controlled, multi-center trials.
In identical 16-week studies 1 and 2, the safety and efficacy of omalizumab as add-on therapy were demonstrated in 1,071 allergic asthmatics, who were symptomatic despite treatment with inhaled corticosteroids (beclomethasone dipropionate 500 to 1,200 micrograms/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 out to one 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 ≥1,000 micrograms/day) and in whom long-acting beta2-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 micrograms/day was 60.3% versus 45.8% in the placebo group.
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 micrograms of Budesonide Turbohaler. Inhaled long-acting beta2-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 ≥1.0 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 ≥1.0 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, ages 12 to 79 years, who had reduced lung function (Forced Expiratory Volume/1 second: FEV1 40 to 80% predicted) and poor asthma symptom control despite receiving >1,000 micrograms of beclomethasone dipropionate (or equivalent) plus long-acting beta2-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 beta2-agonist. Subcutaneous Xolair or placebo were administered as add-on therapy to >1,000 micrograms beclomethasone dipropionate (or equivalent) plus long-acting beta2-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 below 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 five above 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), day and night time symptoms, rescue medication use, spirometry and exacerbations. In all five 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 of age: The primary support for safety and efficacy of Xolair in the 6 to <12 years of age group comes from one randomized, double-blind, placebo controlled, multi-center 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 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 one perennial aeroallergen and a history of clinical features of moderate to severe persistent asthma including daytime and/or night-time symptoms along with a history of experiencing exacerbations within the year prior to study entry. Long-acting beta2-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 I.V. (intravenous)) 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 beta2-agonist use at baseline compared with placebo patients, representing a 45% decrease for long-acting beta2-agonist users and a 42% decrease for long-acting beta2-agonist non-users (p<0.001 and p=0.011, respectively).
Study 7 was a 28 week randomized, double blind, placebo-controlled study primarily evaluating safety in 334 children, aged 6-12 years of age, with asthma who were well controlled with inhaled corticosteroids. During the first 16 weeks of treatment, patients' 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 two above 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, day and night time 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 three randomized, double-blind, placebo controlled, parallel-group, multi-center studies: Q4881g, Q4882g and Q4883g.
Studies Q4881g and Q4882g evaluated efficacy and safety of administration of 75 mg, 150 mg, or 300 mg Xolair every 4 weeks for 24 and 12 weeks respectively, with a 16-week treatment-free follow-up period in patients (12 to 75 years) with refractory CSU despite H1 antihistamine treatment.
Study Q4883g evaluated safety and efficacy of 300 mg Xolair administered every 4 weeks for 24 weeks, with a 16-week treatment-free follow-up period in patients (12 to 75 years) with refractory CSU despite H1 and/or H2 antihistamine and/or leukotriene receptor antagonist (LTRA) treatment. (See Table 1.)
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 (secondary endpoint: see Table 2).
Figure 1 shows the mean weekly itch severity score over time in study Q4881g. The mean weekly itch severity scores significantly decreased in both treatment groups with a maximum effect around week 12 that was sustained over the 24-week treatment period. In studies Q4883g (300 mg over the 24-week treatment period) and Q4882g (150 mg and 300 mg over the 12-week treatment period) the results were similar to those of study Q4881g.
In all three studies (see Figure 1 for study Q4881g), 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. (See Figure 1.)
Time to Minimal Important Difference (MID) response of 5 points in weekly ISS up to week 12: In studies Q4881g and Q4882g the times to attain MID of 5 points on the weekly itch severity score were statistically significantly shorter for patients in the 300 mg treatment groups, compared to the placebo groups with p-value <0.0001. A shorter time was also observed for the 150 mg treatment groups compared to placebo with p=0.0301 in study Q4881g and p=0.0101 in study Q4882g. The median times for attaining MID response were 1 week in the 300 mg treatment group, 2 weeks in the 150 mg groups and 4 weeks for placebo.
Similar results were observed in study Q4883g with p<0.0001 (median time to MID response was 2 weeks in the 300 mg treatment group and 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 (Figure 2 for study Q4881g). Statistical significance (p<0.0001) was achieved in all three 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.
Figure 2 shows 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 three studies (see Figure 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 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. (See Figure 2.)
Proportion of patients with UAS7 ≤ 6 at week 12: The proportions of patients with a UAS7 ≤6 at week 12 are shown in Figure 3. The response rates ranged from 52-66% (300 mg dose), all were statistically significantly higher compared to 11-19% in the placebo group (p<0.0001). The response rates for the 150 mg dose show a notable difference (40-43%; p≤0.001) compared to placebo. (See Figure 3.)
Proportion of patients with UAS7 = 0 at week 12: The proportion of patients with a complete response shown by a UAS7 = 0 at week 12 ranged from 34 to 44% (300 mg dose, statistically significant, all p<0.0001) compared to 5 to 9% in the placebo groups. In the 150 mg treatment groups, a clinically notable difference compared to placebo was observed ranging from 15 to 22% (Figure 4). (See Figure 4.)
Changes from baseline in the weekly number of hives score at week 12: In all three phase III studies, the difference from placebo in mean changes from baseline in the weekly number of hives score at week 12 for the 300 mg treatment groups was statistically significant 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; all p<0.0001). 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 to week 12: In all three Phase III studies the 300 mg treatment groups consistently achieved the highest mean proportion of angioedema-free days from week 4 to week 12 (91 to 96%). The increase in the proportion of angioedema-free days compared to placebo was statistically significant (p<0.001) (Fig 5). In the 150 mg treatment group, the mean proportions of angioedema-free days for the same time period for studies Q4881g and Q4882g were 89.6% and 91.6% respectively. The corresponding placebo values for the same studies were 88.2% and 89.2%. In both of these studies, the differences from placebo did not achieve statistical significance for the 150 mg dose. (See Figure 5.)
Change from baseline to week 12 in overall Dermatology Life Quality Index (DLQI): In all three Phase III studies, the change from baseline to week 12 in the overall DLQI for the 300 mg treatment group was statistically significantly (p<0.001) greater compared to placebo. The 150 mg omalizumab group showed a clinically notable difference to placebo in study Q4882g (Figure 6). (See Figure 6.)
Efficacy after 24 weeks of treatment: Table 3 shows the results after 24 weeks of treatment. Similar magnitudes of response are seen as at 12 weeks. (See Table 3.)
Pharmacokinetics: General characteristics: Absorption: After subcutaneous administration, omalizumab is absorbed with an average absolute bioavailability of 62%. The pharmacokinetics of omalizumab are linear at doses greater than 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 one 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 subcutaneous dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7 to 8 days. Following multiple doses of omalizumab, areas under the serum concentration-time curve from Day 0 to Day 14 at steady state were up to 6-fold of those after the first dose.
Distribution: The apparent volume of distribution of omalizumab in patients with asthma following subcutaneous administration was 78 ± 32 mL/kg.
Elimination: In asthma patients omalizumab serum elimination half-life 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: The population pharmacokinetics of omalizumab 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 to 76 years), race, ethnicity, gender or body mass index.
Patients with Chronic Spontaneous Urticaria (CSU): Absorption: Following a single subcutaneous dose in adult and adolescent patients with CSU, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 6 to 8 days.
In patients with CSU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as a single subcutaneous 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 half-life at steady state averaged 24 days and apparent clearance at steady state averaged 240 mL/day (corresponding to 3.0 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 to 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 (see PRECAUTIONS).
Toxicology: Non-clinical 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: IgE complexes do not fix complement or mediate complement-dependent cytotoxicity.
Chronic administration of omalizumab at dose levels of up to 250 mg/kg (at least 14-fold the highest recommended clinical dose in mg/kg) was well tolerated in non-human primates (both adult and juvenile animals), with the exception of a dose-related decrease in platelet counts that occurred in several non-human 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 hemorrhage and inflammation were observed at injection sites in cynomolgus monkeys, consistent with a localized immune response to repeated subcutaneous administration of a heterologous protein. Formal carcinogenicity studies have not been conducted with omalizumab.
Antibodies to omalizumab were detected in some monkeys following subcutaneous or intravenous 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.
Reproduction, milk excretion and fertility studies in animals are described in USE IN PREGNANCY & LACTATION.
MedsGo Class
Antiasthmatic & COPD Preparations
Features
Brand
Xolair
Full Details
Dosage Strength
150mg / 1.2mL
Drug Ingredients
- Omalizumab
Drug Packaging
Lyophilized Powder for Injection (S.C.) 2ml x 1's
Generic Name
Omalizumab
Dosage Form
Lyophilized Powder For Injection (S.C.)
Registration Number
BR-987
Drug Classification
Prescription Drug (RX)