Novartis Pharmaceuticals UK Ltd

Antibodies to omalizumab have been detected in a low number of patients in clinical trials (see section 4.8). The clinical relevance of anti-Xolair antibodies is not well understood.

 
In Section 4.6 the fertility paragraph has been amended as below:

Fertility

There are no human fertility data for omalizumab. In specifically-designed non-clinical fertility studies, including mating studies, no impairment of male or female fertility and no genotoxicity have been was observed following repeated dosing with omalizumab at dose levels up to 75 mg/kg. Furthermore, no genotoxic effects were observed in separate non-clinical genotoxicity studies (see section 5.3).

In Section 4.8 "anti-therapeutic antibody development" has been added as a rare side effects to the table under "Immune System Disorders".

In Section 5.2 a new paragraph relating to bioequivalence has been added as the last paragraph under "Absorption" sub-heading as follows:

Administration of Xolair manufactured as a lyophilised or liquid formulation resulted in similar serum concentration-time profiles of omalizumab.

In Section 5.3 the following paragraph has been amended as shown below:

Chronic administration of omalizumab athigh dose levels of (up to 250 mg/kg (more than 14-fold the maximum allowable clinical dose of 17.5 mg/kg according to the recommended dosing table) of omalizumab was well tolerated in non-human primates (both adult and juvenile animals), with the exception of a dose-related and age-dependent decrease in blood platelets, with a greater sensitivity in juvenile animals. The serum concentration required to attain a 50% drop in platelets from baseline in adult cynomolgus monkeys was roughly 4- to 20-fold higher than anticipated maximum clinical serum concentrations. In addition, acute haemorrhage and inflammation were observed at injection sites in cynomolgus monkeys.

In Section 6.1 the wording of the excipients for the powder has been amended as follows:

Powder

Sucrose

L-hHistidine

L-hHistidine hydrochloride monohydrate

Polysorbate 20

Discontinuation of omalizumab should be considered in all severe cases with the above mentioned immune system disorders.

Malignancies

During clinical trials in adults and adolescents 12 years of age and older, there was a numerical imbalance in cancers arising in the Xolair (0.5%; 25 cancers in 5,015 patients) treatment group compared with the control (0.18%; 5 cancers in 2,854 patients) group. Malignancies were uncommon (<1/100) in both the active and the control group. The diversity in the type of cancers observed, the relatively short duration of exposure and the clinical features of the individual cases render a causal relationship unlikely. The overall observed incidence rate of malignancy in the Xolair clinical trial programme was comparable to that reported in the general population.

Parasitic (helminth) infections

IgE may be involved in the immunological response to some helminth infections. In patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight increase in infection rate with omalizumab, although the course, severity, and response to treatment of infection were unaltered. The helminth infection rate in the overall clinical programme, 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 travelling to areas where helminthic infections are endemic. If patients do not respond to recommended anti-helminth treatment, discontinuation of Xolair should be considered.

Malignancies

During clinical trials in adults and adolescents 12 years of age and older, there was a numerical imbalance in cancers arising in the Xolair (0.5%; 25 cancers in 5,015 patients) treatment group compared with the control (0.18%; 5 cancers in 2,854 patients) group. Malignancies were uncommon (<1/100) in both the active and the control group. The diversity in the type of cancers observed, the relatively short duration of exposure and the clinical features of the individual cases render a causal relationship unlikely. The overall observed incidence rate of malignancy in the Xolair clinical trial programme was comparable to that reported in the general population.

There were no cases of malignancy with omalizumab in the clinical trials in children 6 to <12 years of age; there was a single case of malignancy in the control group.

Arterial thromboembolic events (ATE)

In controlled clinical trials and an ongoing observational study, a numerical imbalance of ATEs was observed. ATE included stroke, transient ischaemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause). The rate of ATE in patients in the controlled clinical trials was 6.29 for Xolair-treated patients (17/2703 patient years) and 3.42 for control patients (6/1755 patient years). In Cox proportional hazards model, Xolair was not associated with ATE risk (hazard ratio 1.86; 95% confidence interval 0.73‑4.72). In the observational study, the rate of ATE was 5.59 (79/14140 patients years) for Xolair-treated patients and 3.71 (31/8366 patient years) for control patients.In a multivariate analysis controlling for baseline cardiovascular risk factors, Xolair was not associated with ATE risk (hazard ratio 1.11; 95% confidence interval 0.70‑1.76).

Platelets

In clinical trials few patients had platelet counts below the lower limit of the normal laboratory range. None of these changes were associated with bleeding episodes or a decrease in haemoglobin. No pattern of persistent decrease in platelet counts, as observed in non-human primates (see section 5.3), has been reported in humans (patients above 6 years of age), even though isolated cases of idiopathic thrombocytopenia have been reported in the post-marketing setting.

One vial contains 150 mg of omalizumab*.

*Omalizumab is a humanised monoclonal antibody manufactured by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell line.

After reconstitution onethe vial contains 125 mg/ml of omalizumab (150 mg in 1.2 ml).

For a full list of excipients, see section 6.1.

Xolair is indicated in adults, adolescents and children (6 to <12 years of age).

Xolair treatment should only be considered for patients with convincing IgE (immunoglobulin E) mediated asthma (see section 4.2).

Xolair treatment should only be considered for patients with convincing IgE (immunoglobulin E) mediated asthma (see section 4.2).

Xolair treatment should be initiated by physicians experienced in the diagnosis and treatment of severe persistent asthma.

Posology

The appropriate dose and dosing frequency of Xolair is determined by baseline IgE (IU/ml), measured before the start of treatment, and body weight (kg). Prior to administration of the initial dosinge, 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.

Patients with IgE lower than 76 IU/ml were less likely to experience benefit (see section 5.1). Prescribing physicians should ensure that adult and adolescent patients with IgE below 76 IU/ml and childrenpaediatric (6 to < 12 years of age) patients with IgE below 200 IU/ml have unequivocal in vitro reactivity (RAST) to a perennial allergen before starting therapy.

See Table 1 for a conversion chart and Tables 2 and 3 for the dose determination charts in adults, adolescents and children (6 to <12 years of age6 years of age and older).

Patients whose baseline IgE levels or body weight in kilograms are outside the limits of the dosinge table should not be given Xolair.

Treatment duration, monitoring and dose adjustments

Xolair is intended for long-term treatment. Clinical trials have demonstrated that it takes at least 12‑16 weeks for Xolair treatment to show effectiveness. At 16 weeks after commencing Xolair therapy patients should be assessed by their physician for treatment effectiveness before further injections are administered. The decision to continue Xolair following the 16-week timepoint, or on subsequent occasions, should be based on whether a marked improvement in overall asthma control is seen (see section 5.1, Physician’s overall assessment of treatment effectiveness).

Discontinuation of Xolair treatment 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 2 and 3).

Special populations

Elderly (65 years of age and older)

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 dose from younger adult patients.

Renal or hepatic impairment

There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of Xolair. Because omalizumab clearance at clinical doses is dominated by the reticular endothelial system (RES) it is unlikely to be altered by renal or hepatic impairment. While no particular dose adjustment is recommended for these patients, Xolair should be administered with caution (see section 4.4).

Paediatric population

The safety and efficacy of Xolair in children below age 6 have not been established. No data are available.

Method of aAdministration

For subcutaneous administration only. Do not administer by the intravenous or intramuscular route.

The injections are administered subcutaneously in the deltoid region of the arm. Alternatively, the injections can be administered in the thigh if there is any reason precluding administration in the deltoid region.

There is limited experience with self-administration of Xolair. Therefore treatment is intended to be administered by a healthcare provider only.

For instructionsinformation on reconstitution of Xolair before administration, see section 6.6 and also information for the healthcare professional section of the package leaflet.

Treatment duration, monitoring and dose adjustments

Discontinuation of Xolair treatment generally results in a return to elevated free IgE levels and associated symptoms.

Clinical trials have demonstrated that it takes at least 12‑16 weeks for Xolair treatment to show effectiveness. At 16 weeks after commencing Xolair therapy patients should be assessed by their physician for treatment effectiveness before further injections are administered. The decision to continue Xolair should be based on whether a marked improvement in overall asthma control is seen (see section 5.1; Physician’s overall assessment of treatment effectiveness).

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 2 and 3).

Elderly (65 years of age and older)

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.

Children (below 6 years of age)

Xolair is not recommended for use in children below age 6 due to insufficient data on safety and efficacy.

Patients with renal or hepatic impairment

There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of Xolair. Because omalizumab clearance at clinical doses is dominated by the reticular endothelial system (RES) it is unlikely to be altered by renal or hepatic impairment. While no particular dose adjustment is recommended for these patients, Xolair should be administered with caution (see section 4.4).

Xolair has not been studied in patients with hyperimmunoglobulin E syndrome or allergic bronchopulmonary aspergillosis or for the prevention of anaphylactic reactions, including those provoked by food allergy, atopic dermatitis, or allergic rhinitis. Xolair is not indicated for the treatment of these conditions.

Xolair therapy has not been studied in patients with autoimmune diseases, immune complex-mediated conditions, or pre-existing renal or hepatic impairment (see section 4.2). Caution should be exercised when administering Xolair in these patient populations.

Patients with diabetes mellitus, the glucose-galactose malabsorption syndrome, fructose intolerance or sucrase-isomaltase deficiency should be warned that one 150 mg Xolair dose contains 108 mg of sucrose.

As with all recombinant DNA derived humanised monoclonal antibodies, patients may in rare cases develop antibodies to omalizumab.

Antibodies to omalizumab have been detected in a low number of patients in clinical trials. The clinical relevance of anti-Xolair antibodies is not well understood.

·             Serum sSickness

Serum sickness and serum sickness-like reactions, which are delayed allergic type III reactions, have rarely been seen in patients treated with humanizsed monoclonal antibodies including omalizumab. The suggested pathophysiologic mechanism includes immune-complex formation and deposition due to development of antibodies against 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/arthralgias, 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.

·             Churg-Strauss syndrome and hypereosinophilic syndrome

Patients with severe asthma may rarely present systemic hypereosinophilic syndrome or allergic eosinophilic granulomatous vasculitis (Churg-Strauss syndrome), both of which are usually treated with systemic corticosteroids.

In rare cases, patients on therapy with anti-asthma medicinal productsagents, including omalizumab, may present or develop systemic eosinophilia and vasculitis. These events are commonly associated with the reduction of oral corticosteroid therapy.

In clinical studies Xolair was commonly used in conjunction with inhaled and oral corticosteroids, inhaled short-acting and long-acting beta agonists, leukotriene modifiers, theophyllines and oral antihistamines. There was no indication that the safety of Xolair was altered with these other commonly used anti-asthma medicinal productsmedications. Limited data are available on the use of Xolair in combination with specific immunotherapy (hypo-sensitisation therapy). In a clinical trial where Xolair was co-administered with immunotherapy, the safety and efficacy of Xolair in combination with specific immunotherapy were found to be no different to that of Xolair alone.

4.6     Fertility, Ppregnancy and lactation

Pregnancy

There are no adequate data from the use of omalizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Omalizumab crosses the placental barrier and the potential for harm to the foetus is unknown. Omalizumab has been associated with age-dependent decreases in blood platelets in non-human primates, with a greater relative sensitivity in juvenile animals (see section 5.3). Xolair should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is not known whether omalizumab is excreted in human breast milk. Omalizumab is excreted into non-human primate breast milk and risk to the suckling child cannot be excluded. Breast-feeding wWomen should not breast-feed during Xolair therapy.

Fertility

There are no human fertility data for omalizumab. In non-clinical studies, no impairment of fertility and no genotoxicity have been observed (see section 5.3).

Xolair has no or negligible influence on the ability to drive and use machines.Patients receiving Xolair should be warned that if they experience dizziness, fatigue, faintness or drowsiness they should not drive or use machinery.

Section 4.8

Over 4,400 allergic asthma patients were randomised in controlled efficacy trials with Xolair.

Based on clinical experience, about 16% of patients treated with Xolair are expected to experience adverse events.

During clinical trials in adult and adolescent patients 12 years of age and older, the most commonly reported adverse reactions were injection site reactions, including injection site pain, swelling, erythema and pruritus, and headaches. In clinical trials in childrenpatients 6 to <12 years of age, the most commonly reported adverse reactions suspected of being related to the medicinal product were headache, pyrexia and upper abdominal pain. Most of the reactions were mild or moderate in severity.

Table 4 lists the adverse reactions recorded in clinical studies in the total safety population treated with Xolair by MedDRA system organ class and by frequency. Within each frequency grouping, adverse reactionsundesirable effects are presented in order of decreasing seriousness. Frequency categories Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and, rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000). ReactionsEvents reported in the post-marketing setting are listed with frequency not known (cannot be estimated from the available data).

Table 4: Adverse reactions

*: Very common in children 6 to <12 years of age

**: In children 6 to <12 years of age

As present..........

Parasitic infections

In 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 wasere unaltered (see section 4.4).

Section 4.9

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.

If an overdose is suspected, the patient should be monitored for any abnormal signs or symptoms. Medical treatment should be sought and instituted appropriately.

Section 5.1

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: R03DX05

As present...........

In a subgroup analysis, patients with pre-treatment total IgE ≥76 IU/ml were more likely to experience clinically meaningful benefit to Xolair. In these patients in study 1 Xolair reduced the rate of asthma exacerbations by 40% (p = 0.002). In addition more patients had clinically meaningful responses in the total IgE ≥76 IU/ml population across the Xolair severe asthma programme. Table 5 includes results in the study 1 population.

As present..............

Section 5.3

As present..............

In reproduction studies in cynomolgus monkeys, subcutaneous doses up to 75 mg/kg (about 12-fold exposure ratio based on 28-day AUC values at 75 mg/kg versus the clinical maximum dose) did not elicit maternal toxicity, embryotoxicity or teratogenicity when administered throughout organogenesis and did not elicit adverse effects on foetal or neonatal growth when administered throughout late gestation, delivery and nursing.

As present..............

Section 6.3

4 years.

After reconstitution: The chemical and physical stability of the reconstituted medicinal product have 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 medicinal 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 or 4 hours at 30°C.

Section 6.4

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Section 6.6

The lyophilised medicinal product takes 15‑20 minutes to dissolve, although in some cases it may take longer. The fully reconstituted medicinal product will appear clear or slightly opaque and may have a few small bubbles or foam around the edge of the vial. Because of the viscosity of the reconstituted medicinal product care must be taken to withdraw all of the medicinal productWITHDRAW ALL OF THE PRODUCT from the vial before expelling any air or excess solution from the syringe in order to obtain the 1.2 ml.

As present.............

4.       To aid in dissolution after completing step 3, gently swirl the 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 medicinal product is fully dissolved, there should be no visible gel-like particles in the solution. Small bubbles or foam around the edge of the vial are common. The reconstituted medicinal product will appear clear or slightly opaque. Do not use if solid particles are present.

As present...............

8.       The injections are administered subcutaneously in the deltoid region of the arm or the thigh.

Xolair 150 mg powder for solution for injection is supplied in a single-use vial and contains no antibacterial preservatives.

From a microbiological point of view, the medicinal product should be used immediately after reconstitution (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Section 9

Date of first authorisation: 25./10./2005

Date of latest renewal: 25/10/2010

4.2     Posology and method of administration

Xolair treatment should be initiated by physicians experienced in the diagnosis and treatment of severe persistent asthma.

The appropriate dose and dosing frequency of Xolair is determined by baseline IgE (IU/ml), measured before the start of treatment, and body weight (kg). Prior to initial dosing, patients should have their IgE level determined by any commercial serum total IgE assay for their dose assignment. Based on these measurements 75‑375600 mg of Xolair in 1 to 34 injections may be needed for each administration.

Patients with IgE lower than 76 IU/ml were less likely to experience benefit (see section 5.1). Prescribing physicians should ensure that adult and adolescent patients with IgE below 76 IU/ml and paediatric (6 to < 12 years of age) patients with IgE below 200 IU/ml have unequivocal in vitro reactivity (RAST) to a perennial allergen before starting therapy.

See Table 1 for a conversion chart and Tables 2 and 3 for the dose determination charts in adults, and adolescents and children (126 years of age and aboveolder), or Tables 4 and 5 for the dose determination charts in children (6 to <12 years of age).

Patients whose baseline IgE levels or body weight in kilograms are outside the limits of the dosing table should not be given Xolair.

The maximum recommended dose is 375600 mg omalizumab every two weeks.

Table 1: Conversion from dose to number of vials, number of injections and total injection volume for each administration

Adults and adolescents (12 years of age and older)

Table 2: ADMINISTRATION EVERY 4 WEEKS. Xolair doses (milligrams per dose) administered by subcutaneous injection every 4 weeks

Table 3: ADMINSTRATION EVERY 2 WEEKS. Xolair doses (milligrams per dose) administered by subcutaneous injection every 2 weeks

Children (6 to <12 years of age)

Table 4: ADMINISTRATION EVERY 4 WEEKS. Xolair doses (milligrams per dose) administered by subcutaneous injection every 4 weeks in children 6 to <12 years of age

Table 5: ADMINISTRATION EVERY 2 WEEKS. Xolair doses (milligrams per dose) administered by subcutaneous injection every 2 weeks for children 6 to <12 years of age

When a child reaches 12 years of age, modification of dosing is at the physician’s discretion.

Administration

For subcutaneous administration only. Do not administer by the intravenous or intramuscular route.

The injections are administered subcutaneously in the deltoid region of the arm. Alternatively, the injections can be administered in the thigh if there is any reason precluding administration in the deltoid region.

There is limited experience with self-administration of Xolair. Therefore treatment is intended to be administered by a healthcare provider.

For information on reconstitution of Xolair, see section 6.6.

Treatment duration, monitoring and dose adjustments

Discontinuation of Xolair treatment generally results in a return to elevated free IgE levels and associated symptoms.

Clinical trials have demonstrated that it takes at least 12‑16 weeks for Xolair treatment to show effectiveness. At 16 weeks after commencing Xolair therapy patients should be assessed by their physician for treatment effectiveness before further injections are administered. The decision to continue Xolair should be based on whether a marked improvement in overall asthma control is seen (see section 5.1; Physician’s overall assessment of treatment effectiveness).

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 2,  and 3, 4 and 5).

Elderly (65 years of age and older)

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.

Children (below 6 years of age)

Xolair is not recommended for use in children below age 6 due to insufficient data on safety and efficacy.

Patients with renal or hepatic impairment

There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of Xolair. Because omalizumab clearance at clinical doses is dominated by the reticular endothelial system (RES) it is unlikely to be altered by renal or hepatic impairment. While no particular dose adjustment is recommended for these patients, Xolair should be administered with caution (see section 4.4).

4.4     Special warnings and precautions for use

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, including those provoked by food allergy. Xolair is not indicated for the treatment of these conditions.

Xolair therapy has not been studied in patients with autoimmune diseases, immune complex-mediated conditions, or 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.

Patients with diabetes mellitus, the glucose-galactose malabsorption syndrome, fructose intolerance or sucrase-isomaltase deficiency should be warned that one 150 mg Xolair dose contains 108 mg of sucrose.

Immune system disorders

·             Allergic reactions type I

Type I local or systemic allergic reactions, including anaphylaxis and anaphylactic shock, may occur when taking omalizumab, also with onset after a long duration of treatment. Most of these reactions occurred within 2 hours after the first and subsequent injections of Xolair but some started beyond 2 hours and even beyond 24 hours after the injection. Therefore medicinal products for the treatment of anaphylactic reactions should always 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 section 4.8).

As with all recombinant DNA derived humanised monoclonal antibodies, patients may in rare cases develop antibodies to omalizumab.

·             Serum Sickness

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 suggested pathophysiologic mechanism includes immune-complex formation and deposition due to development of antibodies against 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/arthralgias, 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.

·             Churg-Strauss syndrome and hypereosinophilic syndrome

Patients with severe asthma may rarely present systemic hypereosinophilic syndrome or allergic eosinophilic granulomatous vasculitis (Churg-Strauss syndrome), both of which are usually treated with systemic corticosteroids.

In rare cases, patients on therapy with anti-asthma agents, including omalizumab, may present or develop systemic eosinophilia and vasculitis. These events are commonly associated with the reduction of oral corticosteroid therapy.

In these patients, physicians should be alert to the development of marked eosinophilia, vasculitic rash, worsening pulmonary symptoms, paranasal sinus abnormalities, cardiac complications, and/or neuropathy.

Discontinuation of omalizumab should be considered in all severe cases with the above mentioned immune system disorders.

Parasitic (helminth) infections

IgE may be involved in the immunological response to some helminth infections. In patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight increase in infection rate with omalizumab, although the course, severity, and response to treatment of infection were unaltered. The helminth infection rate in the overall clinical programme, 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 travelling to areas where helminthic infections are endemic. If patients do not respond to recommended anti-helminth treatment, discontinuation of Xolair should be considered.

Malignancies

During clinical trials in adults and adolescents 12 years of age and older, there was a numerical imbalance in cancers arising in the Xolair (0.5%; 25 cancers in 5,015 patients) treatment group compared with the control (0.18%; 5 cancers in 2,854 patients) group. Maglignancies were uncommon (<1/100) in both the active and the control group. The diversity in the type of cancers observed, the relatively short duration of exposure and the clinical features of the individual cases render a causal relationship unlikely. The overall observed incidence rate of malignancy in the Xolair clinical trial programme was comparable to that reported in the general population.

4.8     Undesirable effects

Over 4,400 allergic asthma patients were randomised in controlled efficacy trials with Xolair.

Based on clinical experience, about 16% of patients treated with Xolair are expected to experience adverse events.

During clinical trials in adult and adolescent patients 12 years of age and older, the most commonly reported adverse reactions were injection site reactions, including injection site pain, swelling, erythema and pruritus, and headaches. In clinical trials in patients 6 to <12 years of age, the most commonly reported adverse reactions suspected of being related to the medicinal product were headache, pyrexia and upper abdominal pain. Most of the reactions were mild or moderate in severity.

Table 46 lists the adverse reactions recorded in clinical studies in the total safety population treated with Xolair by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (<1/1,000). Events reported in the post-marketing setting are listed with frequency not known (cannot be estimated from the available data).

Table 46: Adverse reactions

*: Very common in children 6 to <12 years of age

**: In children 6 to <12 years of age

Immune system disorders

For further information, see section 4.4.

Malignancies

The overall observed incidence rate of malignancy in adults and in adolescents 12 years of age and older in the Xolair clinical trial programme was comparable to that reported in the general population (see section 4.4).

There were no cases of malignancy with omalizumab in the clinical trials in children 6 to <12 years of age; there was a single case of malignancy in the control group.

Platelets

In clinical trials few patients had platelet counts below the lower limit of the normal laboratory range. None of these changes were associated with bleeding episodes or a decrease in haemoglobin. No pattern of persistent decrease in platelet counts, as observed in non-human primates (see section 5.3), has been reported in humans (patients above 6 years of age), even though isolated cases of idiopathic thrombocytopenia have been reported in the post-marketing setting.

Parasitic infections

In 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 was unaltered (see section 4.4).

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: other systemic drugs for obstructive airway diseases, ATC code: R03DX05

Omalizumab is a recombinant DNA-derived humanised 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.

Omalizumab binds to IgE and prevents binding of IgE to FCeRI (high-affinity IgE receptor), 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 FCeRI receptors on basophils.

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, serum free IgE levels were reduced in a dose-dependent manner within one hour following the first dose and maintained between doses. One year after discontinuation of Xolair dosing, the IgE levels had returned to pre-treatment levels with no observed rebound in IgE levels after washout of the medicinal product.

Clinical experience

Adults and adolescents ≥12 years of age

The efficacy and safety of Xolair were demonstrated in a 28-week double-blind placebo-controlled study (study 1) involving 419 severe allergic asthmatics, ages 12‑79 years, who had reduced lung function (FEV₁ 40‑80% predicted) and poor asthma symptom control despite receiving high dose inhaled corticosteroids and a 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 a long-acting beta2-agonist. Subcutaneous Xolair or placebo were administered as add-on therapy to >1,000 micrograms beclomethasone dipropionate (or equivalent) plus a long-acting beta2-agonist. Oral corticosteroid, theophylline and leukotriene-modifier maintenance therapies were allowed (22%, 27%, and 35% of patients, respectively).

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.

In a subgroup analysis patients with pre-treatment total IgE ≥76 IU/ml were more likely to experience clinically meaningful benefit to Xolair. In these patients in study 1 Xolair reduced the rate of asthma exacerbations by 40% (p = 0.002). In addition more patients had clinically meaningful responses in the total IgE ≥76 IU/ml population across the Xolair severe asthma programme. Table 57 includes results in the study 1 population.

Table 57: Results of study 1

*        marked improvement or complete control

**      p-value for overall distribution of assessment

Study 2 assessed the efficacy and safety of Xolair in a population of 312 severe allergic asthmatics which matched the population in study 1. Treatment with Xolair in this open label study led to a 61% reduction in clinically significant asthma exacerbation rate compared to current asthma therapy alone.

Four additional large placebo-controlled supportive studies of 28 to 52 weeks duration in 1,722 adults and adolescents (studies 3, 4, 5, 6) assessed the efficacy and safety of Xolair in patients with severe persistent asthma. Most patients were inadequately controlled but were receiving less concomitant asthma therapy than patients in studies 1 or 2. Studies 3‑5 used exacerbation as primary endpoint, whereas study 6 primarily evaluated inhaled corticosteroid sparing.

In studies 3, 4 and 5 patients treated with Xolair had respective reductions in asthma exacerbation rates of 37.5% (p = 0.027), 40.3% (p<0.001) and 57.6% (p<0.001) compared to placebo.

In study 6, significantly more severe allergic asthma patients on Xolair were able to reduce their fluticasone dose to £500 micrograms/day without deterioration of asthma control (60.3%) compared to the placebo group (45.8%, p<0.05).

Quality of life scores were measured using the Juniper Asthma-related Quality of Life Questionnaire. For all six studies there was a statistically significant improvement from baseline in quality of life scores for Xolair patients versus the placebo or control group.

Physician’s overall assessment of treatment effectiveness:

Physician’s overall assessment was performed in five of the above studies as a broad measure of asthma control performed by the treating physician. The physician was able to take into account PEF (peak expiratory flow), 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 group aged 6 to <12 years comes from one randomised, double-blind, placebo-controlled, multi-centre trial (study 7).

Study 7 was a placebo-controlled trial which included a specific subgroup (n=235) of patients as defined in the present indication, who were treated with high-dose inhaled corticosteroids (≥500 µg/day fluticasone equivalent) plus long-acting beta agonist).

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 intravenous) corticosteroids for at least 3 days.

In the specific subgroup of patients on high dose inhaled corticosteroids, the omalizumab group had a statistically significantly lower rate of clinically significant asthma exacerbations than the placebo group. At 24 weeks, the difference in rates between treatment groups represented a 34% (rate ratio 0.662, p = 0.047) decrease relative to placebo for omalizumab patients. In the second double-blind 28-week treatment period the difference in rates between treatment groups represented a 63% (rate ratio 0.37, p<0.001) decrease relative to placebo for omalizumab patients.

During the 52-week double-blind treatment period (including the 24-week fixed-dose steroid phase and the 28-week steroid adjustment phase) the difference in rates between treatment groups represented a 50% (rate ratio 0.504, p<0.001) relative decrease in exacerbations for omalizumab patients.

The omalizumab group showed greater decreases in beta-agonist rescue medication use than the placebo group at the end of the 52-week treatment period, although the difference between treatment groups was not statistically significant. For the global evaluation of treatment effectiveness at the end of the 52-week double-blind treatment period in the subgroup of severe patients on high-dose inhaled corticosteroids plus long-acting beta agonists, the proportion of patients rated as having ‘excellent’ treatment effectiveness was higher, and the proportions having ‘moderate’ or ‘poor’ treatment effectiveness lower in the omalizumab group compared to the placebo group; the difference between groups was statistically significant (p<0.001), while there were no differences between the omalizumab and placebo groups for patients’ subjective Quality of Life ratings.

5.2     Pharmacokinetic properties

The pharmacokinetics of omalizumab have been studied in adult and adolescent patients with allergic asthma.

Absorption

After subcutaneous administration, omalizumab is absorbed with an average absolute bioavailability of 62%. Following a single subcutaneous dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 7‑8 days. The pharmacokinetics of omalizumab are linear at doses greater than 0.5 mg/kg. 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

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. The apparent volume of distribution in patients following subcutaneous administration was 78 ± 32  ml/kg.

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 reticuloendothelial system and endothelial cells. Intact IgG is also excreted in bile. In asthma patients the omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 ml/kg/day. In addition, doubling of body weight approximately doubled apparent clearance.

Characteristics in patient populations

Age, Race/Ethnicity, Gender, Body Mass Index

The population pharmacokinetics of Xolair were analysed to evaluate the effects of demographic characteristics. Analyses of these limited data suggest that no dose adjustments are necessary for age (612‑76 years), race, /ethnicity, or gender or Body Mass Index (see section 4.2).

Renal and hepatic impairment

There are no pharmacokinetic or pharmacodynamic data in patients with renal or hepatic impairment (see sections 4.2 and 4.4).

The following reflects changes to SmPC to include the pediatric indication.  

Changes In section 4.1 (therapeutics indications)

Split into two indications; Adults and adolescents (12 years of age and older) and Children (6 to <12 years of age). Which now reads:

Adults and adolescents (12 years of age and older)

Xolair is indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and who have reduced lung function (FEV₁ <80%) as well as frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist.

Children (6 to <12 years of age)

Xolair is indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist.

In section 4.2 (Posology and method of administration)

• The header from the 1^st paragraph has been removed.
• The following wording has been added to paragraphs 3 and 4

Patients with IgE lower than 76 IU/ml were less likely to experience benefit (see section 5.1). Prescribing physicians should ensure that adult and adolescent patients with IgE below 76 IU/ml and paediatric (6 to < 12 years of age) patients with IgE below 200 IU/ml have unequivocal in vitro reactivity (RAST) to a perennial allergen before starting therapy.

See Table 1 for a conversion chart and Tables 2 and 3 for the dose determination charts in adults and adolescents (12 years of age and above), or Tables 4 and 5 for the dose determination charts in children (6 to <12 years of age).

• The following wording has been added under the new subheading Administration;

Administration

For subcutaneous administration only. Do not administer by the intravenous or intramuscular route.

The injections are administered subcutaneously in the deltoid region of the arm. Alternatively, the injections can be administered in the thigh if there is any reason precluding administration in the deltoid region.

There is limited experience with self-administration of Xolair. Therefore treatment is intended to be administered by a healthcare provider.

For information on reconstitution of Xolair, see section 6.6.

• The following information has been added to the text under the subheading: Treatment duration, monitoring and dose adjustments to read;

Clinical trials have demonstrated that it takes at least 12‑16 weeks for Xolair treatment to show effectiveness

Doses should be adjusted for significant changes in body weight (see Tables 2, 3, 4 and 5).

Children (below 6 years of age)

Xolair is not recommended for use in children below age 6 due to insufficient data on safety and efficacy.

Patients with renal or hepatic impairment

There have been no studies on the effect of impaired renal or hepatic function on the pharmacokinetics of Xolair. Because omalizumab clearance at clinical doses is dominated by the reticular endothelial system (RES) it is unlikely to be altered by renal or hepatic impairment. While no particular dose adjustment is recommended for these patients, Xolair should be administered with caution (see section 4.4).

Changes In section 4.4 (Special warnings and precautions for use)

·         Under the subheading General; in paragraph 2. The following text has been added: Xolair is not indicated for the treatment of these conditions.

·        Under the subheading Malignancies; the paragraph has been reworded to read as follows:  During clinical trials in adults and adolescents 12 years of age and older, there was a numerical imbalance in cancers arising in the Xolair (0.5%; 25 cancers in 5,015 patients) treatment group compared with the control (0.18%; 5 cancers in 2,854 patients) group. Malignancies were uncommon (<1/100) in both the active and the control group. The diversity in the type of cancers observed, the relatively short duration of exposure and the clinical features of the individual cases render a causal relationship unlikely. The overall observed incidence rate of malignancy in the Xolair clinical trial programme was comparable to that reported in the general population.

Changes In section 4.5 Interaction with other medicinal products and other forms of interaction

The following has been deleted from paragraph 2:  Efficacy of Xolair treatment in combination with specific immunotherapy has not been established. Current data suggest that no dose adjustments of Xolair are needed in patients on established hypo-sensitisation therapy.

The wording; Xolair may indirectly reduce the efficacy of medicinal products for the treatment of helminthic or other parasitic infections (see section 4.4). Has been added as a third paragraph.

Changes to section 4.6 (Pregnancy and lactation)

The following wording has been deleted from paragraph 2; ‘an effect on’ and ‘Nursing mothers’ To now read:

 It is not known whether omalizumab is excreted in human breast milk. Omalizumab is excreted into non-human primate breast milk and risk to the suckling child cannot be excluded. Breast-feeding women should not breast-feed during Xolair therapy.

Changes in Section 4.8 (undesirable effects)

·        The following has been added to now read:

Over 4,400 allergic asthma patients were randomised in controlled efficacy trials with Xolair.

Based on clinical experience, about 16% of patients treated with Xolair are expected to experience adverse events.

During clinical trials in adult and adolescent patients 12 years of age and older, the most commonly reported adverse reactions were injection site reactions, including injection site pain, swelling, erythema and pruritus, and headaches. In clinical trials in patients 6 to <12 years of age, the most commonly reported adverse reactions suspected of being related to the medicinal product were headache, pyrexia and upper abdominal pain. Most of the reactions were mild or moderate in severity.

Table 6 lists the adverse reactions recorded in clinical studies in the total safety population treated with Xolair by system organ class and by frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and rare (<1/1,000). Events reported in the post-marketing setting are listed with frequency not known (cannot be estimated from the available data).

·         The formatting of the Adverse reactions tables has changed

·         The order of  wording within table 4:Adverse Reactions has changed

·         Pharyngitis has been deleted from ‘respiratory,thoracic and mediastinal disorders’ and added under the section ‘Infections and infestations’

Table 6: Adverse reactions

*: Very common in children 6 to <12 years of age

**: In children 6 to <12 years of age

·        The following has been added to now read:

Malignancies

The overall observed incidence rate of malignancy in adults and in adolescents 12 years of age and older in the Xolair clinical trial programme was comparable to that reported in the general population (see section 4.4).

There were no cases of malignancy with omalizumab in the clinical trials in children 6 to <12 years of age; there was a single case of malignancy in the control group.

Platelets

In clinical trials few patients had platelet counts below the lower limit of the normal laboratory range. None of these changes were associated with bleeding episodes or a decrease in haemoglobin. No pattern of persistent decrease in platelet counts, as observed in non-human primates (see section 5.3), has been reported in humans (patients above 6 years of age), even though isolated cases of idiopathic thrombocytopenia have been reported in the post-marketing setting.

Changes in Section 4.9 (Overdose)

Minor change to wording. From ‘A maximum tolerated dose….’ to ‘Maximum tolerated dose…..’

Changes In Section 5.1 (Pharmacodynamic properties):

·         Addition of the following wording to paragraph 5: of the medicinal product

  and;

Children 6 to <12 years of age

The primary support for safety and efficacy of Xolair in the group aged 6 to <12 years comes from one randomised, double-blind, placebo-controlled, multi-centre trial (study 7).

Study 7 was a placebo-controlled trial which included a specific subgroup (N=235) of patients as defined in the present indication, who were treated with high-dose inhaled corticosteroids (≥500 µg/day fluticasone equivalent) plus long-acting beta agonist.

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 intravenous) corticosteroids for at least 3 days.

In the specific subgroup of patients on high-dose inhaled corticosteroids, the omalizumab group had a statistically significantly lower rate of clinically significant asthma exacerbations than the placebo group. At 24 weeks, the difference in rates between treatment groups represented a 34% (rate ratio 0.662, p = 0.047) decrease relative to placebo for omalizumab patients. In the second double-blind 28-week treatment period the difference in rates between treatment groups represented a 63% (rate ratio 0.37, p<0.001) decrease relative to placebo for omalizumab patients.

During the 52-week double-blind treatment period (including the 24-week fixed-dose steroid phase and the 28-week steroid adjustment phase) the difference in rates between treatment groups represented a 50% (rate ratio 0.504, p<0.001) relative decrease in exacerbations for omalizumab patients.

The omalizumab group showed greater decreases in beta-agonist rescue medication use than the placebo group at the end of the 52-week treatment period, although the difference between treatment groups was not statistically significant. For the global evaluation of treatment effectiveness at the end of the 52-week double-blind treatment period in the subgroup of severe patients on high-dose inhaled corticosteroids plus long-acting beta agonists, the proportion of patients rated as having ‘excellent’ treatment effectiveness was higher, and the proportions having ‘moderate’ or ‘poor’ treatment effectiveness lower in the omalizumab group compared to the placebo group; the difference between groups was statistically significant (p<0.001), while there were no differences between the omalizumab and placebo groups for patients’ subjective Quality of Life ratings.

Changes In Section 5.2 (Pharmacokinetic properties)

Minor changes to the wording in the first paragraph .From ‘The pharmacokinetics of omalizumab have been studied in patients with allergic asthma’ to ‘The pharmacokinetics of omalizumab have been studied in adult and adolescent patients with allergic asthma.’

·  Also included  under the subheading  Characteristics in patient populations. Was the addition of alternative reference sections:

Age, Race/Ethnicity, Gender

The population pharmacokinetics of Xolair were analysed to evaluate the effects of demographic characteristics. Analyses of these limited data suggest that no dose adjustments are necessary for age (12‑76 years), race, ethnicity or gender (see section 4.2).

Renal and hepatic impairment

There are no pharmacokinetic or pharmacodynamic data in patients with renal or hepatic impairment (see sections 4.2 and 4.4).

Changes in Section 5.3 (Preclinical safety data)

Addition of the following wording to paragraph two:

Chronic administration of high dose levels (up to 250 mg/kg) of omalizumab was well tolerated in non-human primates (both adult and juvenile animals), with the exception of a dose-related and age-dependent decrease in blood platelets, with a greater sensitivity in juvenile animals. The serum concentration required to attain a 50% drop in platelets from baseline in adult cynomolgus monkeys was roughly 4 to 20-fold higher than anticipated maximum clinical serum concentrations. In addition, acute haemorrhage and inflammation were observed at injection sites in cynomolgus monkeys.

Section 2 Qualitative and Quantitative composition has changed from ‘For excipients, see section 6.1’ to ‘For a full list of excipients, see section 6.1’

Section 4.4 Special warnings and precautions for use. Has been changed from:

Allergic reactions

Local or systemic allergic reactions, including anaphaylaxis and anaphylactic shock, may occur when taking omalizumanb, also with onset after a long duration of treatment

To:

Immune system disorders

a.       Allergic reactions type I

Type I local or systemic allergic reactions, including anaphaylaxis and anaphylactic shock, may occur when taking omalizumanb, also with onset after a long duration of treatment

The following wording was added after  the sentence ‘As with all recombinant DNA derived humanised monoclonal antibodies, patients may in rare cases develop antibodies to omalizumab’  n section 4.4.