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Xolair 150 mg powder and solvent for solution for injection

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

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 one vial contains 125 mg/ml of omalizumab (150 mg in 1.2 ml).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Xolair is an off-white lyophilised powder.

4. Clinical Particulars

4.1 Therapeutic Indications

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).

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.

4.2 Posology And Method Of Administration

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

Posology

The appropriate dose and 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 dose, 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 children (6 to < 12 years of age) 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 age).

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

The maximum recommended dose is 600 mg omalizumab every two weeks.

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

Dose (mg)

Number of vials

Number of injections

Total injection volume (ml)

 
 

75 mg a

150 mg b

   

75

1c

0

1

0.6

150

0

1

1

1.2

225

1c

1

2

1.8

300

0

2

2

2.4

375

1c

2

3

3.0

450

0

3

3

3.6

525

1c

3

4

4.2

600

0

4

4

4.8

a 0.6 ml = maximum delivered volume per vial (Xolair 75 mg).

       

b 1.2 ml = maximum delivered volume per vial (Xolair 150 mg).

       

c or use 0.6 ml from a 150 mg vial.

       

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

 

Body weight (kg)

                 

Baseline IgE (IU/ml)

>20-25

>25-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90-125

>125-150

75

75

75

150

150

150

150

150

300

300

>100-200

150

150

150

300

300

300

300

300

   

>200-300

150

150

225

300

300

         

>300-400

225

225

300

             

>400-500

225

300

   

ADMINISTRATION EVERY 2 WEEKS

SEE TABLE 3

         

>500-600

300

300

               

>600-700

300

                 

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

 

Body weight (kg)

                 

Baseline IgE (IU/ml)

>20-25

>25-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90-125

>125-150

ADMINISTRATION EVERY 4 WEEKS

SEE TABLE 2

                 

>100-200

     

225

300

         

>200-300

         

225

225

225

300

375

>300-400

     

225

225

225

300

300

450

525

>400-500

   

225

225

300

300

375

375

525

600

>500-600

   

225

300

300

375

450

450

600

 

>600-700

 

225

225

300

375

450

450

525

   

>700-800

225

225

300

375

450

450

525

600

   

>800-900

225

225

300

375

450

525

600

     

>900-1000

225

300

375

450

525

600

       

>1000-1100

225

300

375

450

600

         

>1100-1200

300

300

450

525

600

DO NOT ADMINISTER– data is unavailable for dose recommendation

       

>1200-1300

300

375

450

525

           

>1300-1500

300

375

525

600

           

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 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 only.

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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, 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.

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.

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).

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.

• Serum sickness

Serum sickness and serum sickness-like reactions, which are delayed allergic type III reactions, have been seen in patients treated with humanised 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 products, 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.

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of omalizumab; thus, there is little potential for drug-drug interactions. Medicinal product or vaccine interaction studies have not been performed with Xolair. There is no pharmacological reason to expect that commonly prescribed medicinal products used in the treatment of asthma will interact with omalizumab.

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 products. 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.

Xolair may indirectly reduce the efficacy of medicinal products for the treatment of helminthic or other parasitic infections (see section 4.4).

4.6 Pregnancy 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. Women should not breast-feed during Xolair therapy.

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 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).

4.7 Effects On Ability To Drive And Use Machines

Xolair has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

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

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 children 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 frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequency categories are defined as: very common (

Table 4: Adverse reactions

Infections and infestations

 

Uncommon

Pharyngitis

Rare

Parasitic infection

Blood and lymphatic system disorders

 

Not known

Idiopathic severe thrombocytopenia

Immune system disorders

 

Rare

Anaphylactic reaction, other serious allergic conditions, anti-therapeutic antibody development

Not known

Serum sickness, may include fever and lymphadenopathy

Nervous system disorders

 

Common

Headache*

Uncommon

Syncope, paraesthesia, somnolence, dizziness

Vascular disorders

 

Uncommon

Postural hypotension, flushing

Respiratory, thoracic and mediastinal disorders

 

Uncommon

Allergic bronchospasm, coughing

Rare

Laryngoedema

Not known

Allergic granulomatous vasculitis (i.e. Churg-Strauss syndrome)

Gastrointestinal disorders

 

Common

Abdominal pain upper**

Uncommon

Dyspeptic signs and symptoms, diarrhoea, nausea

Skin and subcutaneous tissue disorders

 

Uncommon

Photosensitivity, urticaria, rash, pruritus

Rare

Angioedema

Not known

Alopecia

Musculoskeletal and connective tissue disorders

 

Not known

Arthralgia, myalgia, joint swelling

General disorders and administration site conditions

 

Very common

Pyrexia**

Common

Injection site reactions such as swelling, erythema, pain, pruritus

Uncommon

Influenza-like illness, swelling arms, weight increase, fatigue

*: 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.

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





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