XOLAIR 150 MG

Israel - English - Ministry of Health

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Active ingredient:
OMALIZUMAB
Available from:
NOVARTIS ISRAEL LTD
ATC code:
R03DX05
Pharmaceutical form:
POWDER AND SOLVENT FOR SOLUTION FOR INJECTION
Composition:
OMALIZUMAB 150 MG/DOSE
Administration route:
S.C
Prescription type:
Required
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
Therapeutic group:
OMALIZUMAB
Therapeutic area:
OMALIZUMAB
Therapeutic indications:
Allergic asthma Xolair is indicated for patients 6 to 12 years of age with severe persistent asthma and for patients 12 years of age and older with moderate to severe persistent asthma, who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Xolair has been shown to decrease the incidence of asthma exacerbations in these patients. Limitations of use: Xolair is not indicated for the relief of acute bronchospasm or status asthmaticus. Xolair is not indicated for the treatment of other allergic conditions.Chronic rhinosinusitis with nasal polyps (CRSwNP) Xolair is indicated as an add-on therapy with intranasal corticosteroids (INC) for the treatment of adults (18 years and above) with severe CRSwNP for whom therapy with INC does not provide adequate disease control.Chronic spontaneous urticaria (CSU) Xolair is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and adolescent
Authorization number:
132 61 31124 00
Authorization date:
2015-02-28

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ(

05.2013

)

ךיראת

02.07.2014

םושירה רפסמו תילגנאב רישכת םש

Xolair 150mg, powder for solution for injection, 132 61 31124

:םושירה לעב םש

י'ג ייא ססיורס המראפ סיטרבונ !דבלב תורמחהה טוריפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Indication

-

contraindications

Posology, dosage &

administration

-

Special Warnings and

Special Precautions for Use

Interaction with Other

Medicaments and Other

Forms of Interaction

-

Fertility, Pregnancy and

Lactation

Adverse events

Non-Clinical Safety -

Carcinogenesis,

Mutagenesis, Impairment

of Fertility

Carcinogenesis, Mutagenesis,

Impairment of Fertility

…….

תפסות

Non-Clinical Safety -

Carcinogenesis, Mutagenesis,

Impairment of Fertility

……

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.

….

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NAME OF THE MEDICINAL PRODUCT

XOLAIR

®

150mg

Omalizumab

Powder and solvent for solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 150 mg of omalizumab*.

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

*Omalizumab is a humanised monoclonal antibody manufactured by recombinant DNA technology in

a Chinese hamster ovary (CHO) mammalian cell line.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Powder: white to off-white lyophilisate

Solvent: clear and colourless solution

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Allergic asthma

Xolair is indicated for patients 6 to 12 years of age with severe persistent asthma and for patients 12 years

of age and older with moderate to severe persistent asthma, who have a positive skin test or

in vitro

reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled

corticosteroids. Xolair has been shown to decrease the incidence of asthma exacerbations in these patients.

Limitations of use:

Xolair is not indicated for the relief of acute bronchospasm or status asthmaticus.

Xolair is not indicated for the treatment of other allergic conditions.

Chronic spontaneous urticaria (CSU)

Xolair is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and

adolescent (12 years and above) patients with inadequate response to H1 antihistamine treatment.

4.2 Posology and method of administration

Xolair treatment should be initiated by physicians experienced in the diagnosis and treatment of moderate to severe

persistent asthma or chronic spontaneous urticaria.

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Allergic 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.

See Table 1 for a conversion chart and the dose determination tables below (Table 2, Table 3, Table 4,

Table 5 and Table 6) for appropriate dose assignment.

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.

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)

150 mg

To make up the correct injection volume

use 0.6 ml from one Xolair 150 mg vial.

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

Severe Asthma - 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 for adults and adolescents (12 Years of age and older) with Severe

Asthma

Body weight (kg)

Baseline

IgE

(IU/ml)

>25-

>30- 4

>40- 5

>50- 6

>60- 7

>70- 8

>80- 9

>90-

>125-

30-100

>100-200

>200-300

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>300-400

>400-500

>500-600

>600-700

>700-800

>800-900

ADMINISTRATION EVERY 2 WEEKS

SEE TABLE 3

>900-

1000

>1000-

1100

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

subcutaneous injection every 2 weeks for adults and adolescents (12 Years of age and older) with Severe

Asthma

Body weight (kg)

Baseline

IgE

(IU/ml)

>25-

>30- 4

>40-

>50- 6

>60- 7

>70- 8

>80- 9

>90-

>125-

30-100

ADMINISTRATION EVERY 4 WEEKS

SEE TABLE 2

>100-200

>200-300

>300-400

>400-500

>500-600

>600-700

>700-800

>800-900

>900-

1000

>1000-

1100

>1100-

1200

DO NOT ADMINISTER– data is

unavailable for dose recommendation

>1200-

1300

>1300-

1500

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Moderate Asthma - Adults and Adolescents (12 years of age and older)

Table 4: ADMINISTRATION EVERY 4 WEEKS Xolair Doses (milligrams) Administered by

Subcutaneous Injection Every 4 Weeks for Adults and Adolescents (12 Years of Age and Older)

with Moderate Asthma

Pre-treatment

Serum IgE

Baseline IgE (IU/ml)

Body weight (kg)

30-60

> 60-70

> 70-90

> 90-150

≥30-100

> 100-200

> 200-300

> 300-400

SEE TABLE 5

> 400-500

> 500-600

Table 5: ADMINISTRATION EVERY 2 WEEKS Xolair Doses (milligrams) Administered

by Subcutaneous Injection Every 2 Weeks for Adults and Adolescents (12 Years of Age and

Older) with Moderate Asthma

Pre-treatment

Serum IgE

(IU/mL)

Baseline IgE (IU/ml)

Body weight (kg)

30-60

> 60-70

> 70-90

> 90-150

≥30-100

> 100-200

SEE TABLE 4

> 200-300

> 300-400

> 400-500

> 500-600

Insufficient Data to Recommend

a Dose

> 600-700

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Severe Asthma - Pediatric patients (ages of 6 to <12 years)

Pediatric patients (ages of 6 to <12 years): Initiate dosing according to Table 6.

Table 6: Subcutaneous Xolair Doses Every 2 or 4 Weeks* for Pediatric Patients (ages of 6 to <12

years) with Severe Asthma Who Begin Xolair Treatment.

Pre-treatment

Serum IgE

(IU/mL)

Dosing

Freq.

Body Weight

20-25

>25-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90-125

>125-150

Dose (mg)

30-100

Every 4

weeks

>100-200

>200-300

>300-400

>400-500

>500-600

>600-700

>700-800

Every 2

weeks

Insufficient Data

to Recommend a Dose

>800-900

>900-1000

>1000-1100

>1100-1200

>1200-1300

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 time point, 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 2,3,4,5 and 6).

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Chronic spontaneous urticaria (CSU)

Posology

The recommended dose is 300 mg by subcutaneous injection every four weeks.

Prescribers are advised to periodically reassess the need for continued therapy.

Clinical trial experience of long-term treatment beyond 6 months in this indication is limited.

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 omalizumab. 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

In allergic asthma, the safety and efficacy of Xolair in paediatric patients below the age of 6 years have

not been established. No data are available.

In CSU, the safety and efficacy of Xolair in paediatric patients below the age of 12 years have not been

established.

Method of administration

For subcutaneous administration only. Xolair must not be administered by the intravenous or

intramuscular route.

Doses of more than 150 mg (Table 1) should be divided across two or more injection sites.

There is limited experience with self-administration of Xolair powder and solvent for solution for

injection. Therefore treatment with this formulation is intended to be administered by a healthcare

provider only.

For instructions on reconstitution of the medicinal product 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 listed in section 6.1.

4.4 Special warnings and precautions for use

General

Xolair is not indicated for the treatment of acute asthma exacerbations, acute bronchospasm or status

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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, even after a long duration of treatment. However, 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. The majority of anaphylactic reactions occurred within the

first 3 doses of Xolair. A history of anaphylaxis unrelated to omalizumab may be a risk factor for

anaphylaxis following Xolair administration. Therefore medicinal products for the treatment of

anaphylactic reactions should always be available for immediate use following administration of Xolair. If

an anaphylactic or other serious allergic reaction occurs, administration of Xolair must be discontinued

immediately and appropriate therapy initiated. Patients should be informed that such reactions are possible

and prompt medical attention should be sought if allergic reactions occur.

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.

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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 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 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

Since IgE may be involved in the immunological response to some helminth infections, Xolair may

indirectly reduce the efficacy of medicinal products for the treatment of helminthic or other parasitic

infections (see section 4.4).

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 or

CSU will interact with omalizumab.

Allergic asthma

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.

Chronic spontaneous urticaria (CSU)

In clinical studies in CSU, Xolair was used in conjunction with antihistamines (anti-H1, anti-H2) and

leukotriene receptor antagonists (LTRAs). There was no evidence that the safety of omalizumab was

altered when used with these medicinal products relative to its known safety profile in allergic asthma. In

addition, a population pharmacokinetic analysis showed no relevant effect of H2 antihistamines and

LTRAs on omalizumab pharmacokinetics (see section 5.2).

Paediatric population

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Clinical studies in CSU included some patients aged 12 to 17 years taking Xolair in conjunction with

antihistamines (anti-H1, anti-H2) and LTRAs. No studies have been performed in children under 12 years.

4.6 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) based on

pregnancy registry and post-marketing spontaneous reports, indicates no malformative or foeto/neonatal

toxicity. A prospective pregnancy registry study (EXPECT) in 250 pregnant women with asthma exposed

to Xolair showed the prevalence of major congenital anomalies was similar (8.1% vs. 8.9%) between

EXPECT and disease-matched (moderate and severe asthma) patients. The interpretation of data may be

impacted due to methodological limitations of the study, including small sample size and non-randomised

design.

Omalizumab crosses the placental barrier. However, animal studies do not indicate either direct or indirect

harmful effects with respect to reproductive toxicity (see section 5.3).

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).

If clinically needed, the use of Xolair may be considered during pregnancy.

Breast-feeding

Immunoglobulins G (IgGs) are present in human milk and therefore it is expected that omalizumab will be

present in human milk. Available data in non-human primates have shown excretion of omalizumab into

milk (see section 5.3).

The EXPECT study, with 154 infants who had been exposed to Xolair during pregnancy and through

breast-feeding did not indicate adverse effects on the breast-fed infant. The interpretation of data may be

impacted due to methodological limitations of the study, including small sample size and non-randomised

design.

Given orally, immunoglobulin G proteins undergo intestinal proteolysis and have poor bioavailability. No

effects on the breast-fed newborns/infants are anticipated. Consequently, if clinically needed, the use of

Xolair may be considered during breast-feeding.

Fertility

There are no human fertility data for omalizumab. In specifically-designed non-clinical fertility studies, in

non-human primates 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 a separate non-clinical genotoxicity study.

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

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Allergic asthma

Summary of safety profile

During clinical trials in 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 trials in children 6 to <12 years of age, the most commonly

reported adverse reactions were headache, pyrexia and upper abdominal pain. Most of the reactions were

mild or moderate in severity.

Tabulated list of adverse reactions

Table 7 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

(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to

<1/1,000) and very rare (<1/10,000). Reactions reported in the post-marketing setting are listed with

frequency not known (cannot be estimated from the available data).

Table 7: Adverse reactions in allergic asthma

Infections and infestations

Uncommon

Pharyngitis

Rare

Parasitic infection

Blood and lymphatic system disorders

Not known

Idiopathic thrombocytopenia, including severe cases

Immune system disorders

Rare

Anaphylactic reaction, other serious allergic conditions,

anti-omalizumab 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

Rare

Systemic lupus erythematosus (SLE)

Not known

Arthralgia, myalgia, joint swelling

General disorders and administration site conditions

Very common

Pyrexia**

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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

Chronic spontaneous urticaria (CSU)

Summary of safety profile

The safety and tolerability of omalizumab were investigated with doses of 75 mg, 150 mg and 300 mg

every four weeks in 975 CSU patients, 242 of whom received placebo. Overall, 733 patients were treated

with omalizumab for up to 12 weeks and 490 patients for up to 24 weeks. Of those,

412 patients were treated for up to 12 weeks and 333 patients were treated for up to 24 weeks at the

300 mg dose.

Tabulated list of adverse reactions

A separate table (Table 8) shows the adverse reactions for the CSU indication resulting from differences

in dosages and treatment populations (with significantly different risk factors, comorbidities, co-

medications and ages [e.g. asthma trials included children from 6-12 years of age]).

Table 8 lists the adverse reactions (events occurring in ≥1% of patients in any treatment group and ≥2%

more frequently in any omalizumab treatment group than with placebo (after medical review)) reported

with 300 mg in the three pooled phase III studies. The adverse reactions presented are divided into two

groups: those identified in the 12-week and the 24-week treatment periods.

The adverse reactions are listed by MedDRA system organ class. 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: 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) and not known (cannot be estimated from the available data).

Table 8: Adverse reactions from the pooled CSU safety database (day 1 to week 24) at 300 mg Omalizumab

12-Week

Omalizumab studies 1, 2 and 3 Pooled

Frequency category

Placebo N=242

300 mg N=412

Infections and infestations

Sinusitis

5 (2.1%)

20 (4.9%)

Common

Nervous system disorders

Headache

7 (2.9%)

25 (6.1%)

Common

Musculoskeletal and connective tissue disorders

Arthralgia

1 (0.4%)

12 (2.9%)

Common

General disorder and administration site conditions

Injection site reaction*

2 (0.8%)

11 (2.7%)

Common

24-Week

Omalizumab studies 1 and 3 Pooled

Frequency category

Placebo N=163

300 mg N=333

Infections and infestations

Upper respiratory tract

infection

5 (3.1%)

19 (5.7%)

Common

* Despite not showing a 2% difference to placebo, injection site reactions were included as all cases were assessed

causally related to study treatment.

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Description of selected adverse reactions 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

below.

Immune system disorders

For further information, see section 4.4.

Anaphylaxis

Anaphylactic reactions were rare in clinical trials. However, post-marketing data following a cumulative

search in the safety database retrieved a total of 898 anaphylaxis cases. Based on an estimated exposure of

566,923 patient treatment years, this results in a reporting rate of approximately

0.20%.

Arterial thromboembolic events (ATE)

In controlled clinical trials and during interim analyses of an observational study, a numerical imbalance

of ATE was observed. The definition of the composite endpoint ATE included stroke, transient ischaemic

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 patient 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 0.91-1.91). In a separate analysis of pooled clinical trials, which

included all randomised double-blind, placebo-controlled clinical trials lasting 8 or more weeks, the rate

of ATE per 1,000 patient years was 2.69 (5/1,856 patient years) for Xolair-treated patients and

2.38 (4/1,680 patient years) for placebo patients (rate ratio 1.13, 95% confidence interval 0.24-5.71).

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, including severe cases, have been reported in the post-marketing setting.

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 section 4.4).

Systemic lupus erythematosus

Clinical trial and post-marketing cases of systemic lupus erythematosus (SLE) have been reported in

patients with moderate to severe asthma and CSU. The pathogenesis of SLE is not well understood.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events

should be reported to the Ministry of Health according to the National Regulation by using an online form

https://sideeffects.health.gov.il/

4.9 Overdose

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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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, 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.

Allergic asthma

Mechanism of action

Omalizumab binds to IgE and prevents binding of IgE to Fc

RI (high-affinity IgE receptor) on basophils

and mast cells, 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 Fc

RI receptors

on basophils.

Pharmacodynamic effects

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 allergic asthma patients, 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.

Chronic spontaneous urticaria (CSU)

Mechanism of action

Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcεRI) on cells down-

regulate. It is not entirely understood how this results in an improvement of CSU symptoms.

Pharmacodynamic effect

In clinical studies in CSU 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. After discontinuation of Xolair, free IgE levels increased

towards pre-treatment levels over a 16-week treatment-free follow-up period

Clinical efficacy and safety in allergic asthma

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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

(FEV

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 9 includes results in the

study 1 population.

Table 9: Results of study 1

Whole study 1

population

Xolair

N=209

Placebo

N=210

Asthma exacerbations

Rate per 28-week period

0.74

0.92

% reduction, p-value for rate ratio

19.4%, p = 0.153

Severe asthma exacerbations

Rate per 28-week period

0.24

0.48

% reduction, p-value for rate ratio

50.1%, p = 0.002

Emergency visits

Rate per 28-week period

0.24

0.43

% reduction, p-value for rate ratio

43.9%, p = 0.038

Physician’s overall assessment

% responders*

60.5%

42.8%

p-value**

<0.001

AQL improvement

% of patients ≥0.5 improvement

60.8%

47.8%

p-value

0.008

marked improvement or complete control

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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.

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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.

Clinical efficacy and safety in chronic spontaneous urticaria (CSU)

The efficacy and safety of Xolair were demonstrated in two randomised, placebo-controlled phase III

studies (study 1 and 2) in patients with CSU who remained symptomatic despite H1 antihistamine therapy

at the approved dose. A third study (study 3) primarily evaluated the safety of Xolair in patients with CSU

who remained symptomatic despite treatment with H1 antihistamines at up to four times the approved

dose and H2 antihistamine and/or LTRA treatment. The three studies enrolled 975 patients aged between

12 and 75 years (mean age 42.3 years; 39 patients 12-17 years, 54 patients ≥65 years; 259 males and 716

females). All patients were required to have inadequate symptom control, as assessed by a weekly

urticaria activity score (UAS7, range 0-42) of ≥16, and a weekly itch severity score (which is a component

of the UAS7; range 0-21) of ≥8 for the 7 days prior to randomisation, despite having used an antihistamine

for at least 2 weeks beforehand.

In studies 1 and 2, patients had a mean weekly itch severity score of between 13.7 and 14.5 at baseline and

a mean UAS7 score of 29.5 and 31.7 respectively. Patients in safety study 3 had a mean weekly itch

severity score of 13.8 and a mean UAS7 score of 31.2 at baseline. Across all three studies, patients

reported receiving on average 4 to 6 medications (including H1 antihistamines) for CSU symptoms prior

to study enrollment. Patients received Xolair at 75 mg, 150 mg or 300 mg or placebo by subcutaneous

injection every 4 weeks for 24 and 12 weeks in studies 1 and 2, respectively, and 300 mg or placebo by

subcutaneous injection every 4 weeks for 24 weeks in study 3. All studies had a 16-week treatment-free

follow-up period.

The primary endpoint was the change from baseline to week 12 in weekly itch severity score.

Omalizumab at 300 mg reduced the weekly itch severity score by 8.55 to 9.77 (p <0.0001) compared to a

reduction of 3.63 to 5.14 for placebo (see Table 10). Statistically significant results were further observed

in the responder rates for UAS7≤6 (at week 12) which were higher for the 300 mg treatment groups,

ranging from 52-66% (p<0.0001) compared to 11-19% for the placebo groups, and complete response

(UAS7=0) was achieved by 34-44% (p<0.0001) of patients treated with 300 mg compared to 5-9% of

patients in the placebo groups. Patients in the 300 mg treatment groups achieved the highest mean

proportion of angioedema-free days from week 4 to week 12, (91.0-96.1%; p<0.001) compared to the

placebo groups (88.1-89.2%). Mean change from baseline to week 12 in the overall DLQI for the 300 mg

treatment groups was greater (p<0.001) than for placebo showing an improvement ranging from 9.7-10.3

points compared to 5.1-6.1 points for the corresponding placebo groups.

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Table 10: Change from baseline to week 12 in weekly itch severity score, studies 1, 2 and 3

(mITT population*)

Placebo

Omalizumab

300 mg

Study 1

Mean (SD)

−3.63 (5.22)

−9.40 (5.73)

Difference in LS means vs. placebo

−5.80

95% CI for difference

−7.49,−4.10

P-value vs. placebo

<0.0001

Study 2

Mean (SD)

−5.14 (5.58)

−9.77 (5.95)

Difference in LS means vs. placebo

−4.81

95% CI for difference

−6.49,−3.13

P-value vs. placebo

<0.0001

Study 3

Mean (SD)

−4.01 (5.87)

−8.55 (6.01)

Difference in LS means vs. placebo

-4.52

95% CI for difference

−5.97, −3.08

P-value vs. placebo

<0.0001

*Modified intent-to-treat (mITT) population: included all patients who were randomised and received

at least one dose of study medication.

BOCF (Baseline Observation Carried Forward) was used to impute missing data.

The LS mean was estimated using an ANCOVA model. The strata were baseline weekly itch

severity score (<13 vs. ≥13) and baseline weight (<80 kg vs. ≥80 kg).

p-value is derived from ANCOVA t-test.

Figure 1 shows the mean weekly itch severity score over time in study 1. The mean weekly itch severity

scores significantly decreased with a maximum effect around week 12 that was sustained over the 24-

week treatment period. The results were similar in study 3.

In all three studies the mean weekly itch severity score 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.

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Figure 1: Mean weekly itch severity score over time, study 1 (mITT population)

BOCF=baseline observation carried forward; mITT=modified intention-to-treat population

Efficacy after 24 weeks of treatment

The magnitude of the efficacy outcomes observed at week 24 of treatment was comparable to that

observed at week 12:

For 300 mg, in studies 1 and 3, the mean decrease from baseline in weekly itch severity score was 9.8 and

8.6, the proportion of patients with UAS7≤6 was 61.7% and 55.6%, and the proportion of patients with

complete response (UAS7=0) was 48.1% and 42.5%, respectively, (all p<0.0001, when compared to

placebo).

There is limited clinical experience in re-treatment of patients with omalizumab.

Clinical trial data on adolescents (12 to 17 years) included a total of 39 patients, of whom 11 received the

300 mg dose. Results for the 300 mg are available for 9 patients at week 12 and 6 patients at week 24, and

show a similar magnitude of response to omalizumab treatment compared to the adult population. Mean

change from baseline in weekly itch severity score showed a reduction of 8.25 at week 12 and of 8.95 at

week 24. The responder rates were: 33% at week 12 and 67% at week 24 for UAS7=0, and 56% at week

12 and 67% at week 24 for UAS7≤6.

5.2 Pharmacokinetic properties

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

asthma as well as in adult and adolescent patients with CSU. The general pharmacokinetic characteristics

of omalizumab are similar in these populations.

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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 or CSU,

omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 6-8 days. In

patients with asthma, 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.

The pharmacokinetics of omalizumab are linear at doses greater than 0.5 mg/kg. Following doses of

75 mg, 150 mg or 300 mg every 4 weeks in patients with CSU, trough serum concentrations of

omalizumab increased proportionally with the dose level.

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

in vivo

Based on population pharmacokinetics, distribution of omalizumab was similar in patients with allergic

asthma and patients with CSU. The apparent volume of distribution in patients with asthma 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

ml/kg/day. Doubling of body weight approximately doubled apparent clearance.

In CSU patients, based on population pharmacokinetic simulations, omalizumab serum elimination half-

life at steady state averaged 24 days and apparent clearance at steady state for a patient of 80 kg weight

was 3.0 ml/kg/day.

Characteristics in patient populations

Patients with asthma

The population pharmacokinetics of omalizumab were analysed to evaluate the effects of demographic

characteristics. Analyses of these limited data suggest that no dose adjustments are necessary in patients

with asthma for age ( 6-76 years), race/ethnicity, gender or body mass index (see section 4.2).

Patients with CSU

The effects of demographic characteristics and other factors on omalizumab exposure were evaluated

based on population pharmacokinetics. In addition, covariate effects were evaluated by analysing the

relationship between omalizumab concentrations and clinical responses.

These analyses suggest that no dose adjustments are necessary in patients with CSU for age (12-75 years),

race/ethnicity, gender, body weight, body mass index, baseline IgE, anti-Fc

RI autoantibodies or

concomitant use of H2 antihistamines or LTRAs.

Renal and hepatic impairment

There are no pharmacokinetic or pharmacodynamic data in allergic asthma or CSU patients with renal or

hepatic impairment (see sections 4.2 and 4.4).

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5.3 Preclinical safety data

The safety of omalizumab has been studied in the cynomolgus monkey, since omalizumab binds to

cynomolgus and human IgE with similar affinity. Antibodies to omalizumab were detected in some

monkeys following repeated subcutaneous or intravenous administration. However, no apparent toxicity,

such as immune complex-mediated disease or complement-dependent cytotoxicity, was seen.

There was no evidence of an anaphylactic response due to mast-cell degranulation in cynomolgus

monkeys.

Chronic administration of omalizumab at dose levels of up to 250 mg/kg (at least 14 times the highest

recommended clinical dose in mg/kg according to the recommended dosing table) 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.

Formal carcinogenicity studies have not been conducted with omalizumab.

In reproduction studies in cynomolgus monkeys, subcutaneous doses up to 75 mg/kg per week (at least 8

times the highest recommended clinical dose in mg/kg over a 4 week period) 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.

Omalizumab is excreted in breast milk in cynomolgus monkeys. Milk levels of omalizumab were 0.15%

of the maternal serum concentration.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder

Sucrose 108mg/1.2mL

L-histidine hydrochloride monohydrate

L-histidine

Polysorbate 20

Solvent

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

6.3 Shelf life

The expiry date of the product is printed on the package materials.

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After reconstitution

The chemical and physical stability of the reconstituted medicinal product have been demonstrated for 8

hours at 2°C to 8°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 2 hours at

25°C.

6.4 Special precautions for storage

Store in a refrigerator (2

C - 8

Do not freeze.

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

6.5 Nature and contents of container

Powder vial: Clear, colourless type I glass vial with a chlorobutyl rubber stopper and blue flip-off seal.

Solvent ampoule: Clear, colourless type I glass ampoule containing 2 ml water for injections.

Packs containing 1 vial of powder and 1 ampoule of water for injections, respectively.

6.6 Special precautions for disposal and other handling

Xolair 150 mg powder for solution for injection is supplied in a single-use vial.

From a microbiological point of view, the medicinal product should be used immediately after

reconstitution (see section 6.3).

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 to slightly opalescent, colorless to pale

brownish-yellow 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

product from the vial before expelling any air or excess solution from the syringe in order to obtain the 1.2

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

requirements.

7. Manufacturer:

Novartis Pharma Stein AG, Stein, Switzerland

For: Novartis Pharma AG, Basel, Switzerland.

8. Registration number:

132 61 31124.

9. Registration Holder:

Novartis Israel Ltd., P.O.B 7126, Tel Aviv

Revised in August 2020.

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INFORMATION FOR THE HEALTHCARE PROFESSIONAL

The following information is intended for healthcare professionals only:

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 to slightly opalescent, colourless to

pale brownish-yellow 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

product from the vial before expelling any air or excess solution from the syringe in order to obtain the

1.2 ml.

To prepare Xolair 150 mg vials for subcutaneous administration, please adhere to the following

instructions:

1. Draw 1.4 ml of water for injections from the ampoule into a 3 ml 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 vial containing the lyophilised powder using standard aseptic techniques, directing the water for

injections directly onto the powder.

3. Keeping the vial in an upright position, vigorously swirl it (do not shake) for approximately

1 minute to evenly wet the powder.

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 to lightly opalescent, colourless to pale brownish-yellow. Do not use if solid particles are

present.

5. Invert the vial for at least 15 seconds in order to allow the solution to drain towards the stopper.

Using a new 3-ml syringe equipped with large-bore, 18-gauge needle, insert the needle into the inverted

vial. Keeping the vial inverted position the needle tip at the very bottom of the solution in the vial 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, it may take 5-10 seconds to administer the solution by subcutaneous injection.

The vial delivers 1.2 ml (150 mg) of Xolair. For a 75 mg dose, draw up 0.6 ml into the syringe and discard

the remaining solution.

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

the lower abdomen (but

not the area 5 centimetres around the navel),

or the thigh.

,ה/דבכנ ת/חקור ,ה/דבכנ ה/אפור

:ןודנה

olair 150mg, powder and solvent for solution for injection

X

רייאלוז

150

הקרזהל הסימת תנכהל סממו הקבא ,ג"מ

לע עידוהל םישקבמ ונא רושיא תבחרה

היוותה

לופיט המתסאב

ליגב םידליב

ו ,הלעמו םינש אפורל ןולעה ןוכדע

רישכת .ןודנבש

לארשיב םושר רישכתה תויוותהל

תואבה

Allergic asthma

Xolair is indicated for patients 6 to 12 years of age with severe persistent asthma and for patients 12 years

of age and older with moderate to severe persistent asthma, who have a positive skin test or

in vitro

reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled

corticosteroids. Xolair has been shown to decrease the incidence of asthma exacerbations in these patients.

Limitations of use:

Xolair is not indicated for the relief of acute bronchospasm or status asthmaticus.

Xolair is not indicated for the treatment of other allergic conditions.

Chronic spontaneous urticaria (CSU)

Xolair is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and

adolescent (12 years and above) patients with inadequate response to H1 antihistamine treatment.

ליעפה ביכרמה

Omalizumab 150mg

ףסונב תיוותה תפסותל המתסא

םאתהב ןונימ רטשמ תפסותו םידליב ינוכדעל טרפ ) הלא םינוכדע .םיפסונ םינוכדע ללוכ ןולעה , הכירע

ןולעב תורמחה .םיאבה םידומעב "םייוניש רחא בוקע"ב םיפקושמ תונמוסמ

.בוהצ עבצב

ולעה

אפורל חלשנ

ןתינו ,תואירבה דרשמ רתאבש תופורתה רגאמל ולבקל

ספדומ

לע

.םושירה לעבל הינפ ידי

,הכרבב

ןילטיג הנלי

הנוממ תחקור

Novartis Israel Ltd.

6 Totzeret Ha’arets St.

P.O.B 7126, Tel Aviv, Israel

Tel: 972-3-9201123 Fax: 972-3-9229331

מ"עב לארשי סיטרבונ

'חר ץראה תרצות

.ד.ת

7126

ביבא לת

:ןופלט

03-9201123

:סקפ

03-9229331

NAME OF THE MEDICINAL PRODUCT

XOLAIR

®

150mg

Omalizumab

Powder and solvent for solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 150 mg of omalizumab*.

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

*Omalizumab is a humanised monoclonal antibody manufactured by recombinant DNA technology in

a Chinese hamster ovary (CHO) mammalian cell line.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Powder: white to off-white lyophilisate

Solvent: clear and colourless solution

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Allergic asthma

Xolair is indicated for patients 6 to 12 years of age with severe persistent asthma and for patients 12 years

of age and older with moderate to severe persistent asthma, who have a positive skin test or

in vitro

reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled

corticosteroids. Xolair has been shown to decrease the incidence of asthma exacerbations in these patients.

Limitations of use:

Xolair is not indicated for the relief of acute bronchospasm or status asthmaticus.

Xolair is not indicated for the treatment of other allergic conditions.

Chronic spontaneous urticaria (CSU)

Xolair is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and

adolescent (12 years and above) patients with inadequate response to H1 antihistamine treatment.

4.2 Posology and method of administration

Xolair treatment should be initiated by physicians experienced in the diagnosis and treatment of moderate to severe

persistent asthma or chronic spontaneous urticaria.

Allergic 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.

See Table 1 for a conversion chart and the dose determination tables below (Table 2, Table 3, Table 4,

Table 5 and Table 6) for appropriate dose assignment.

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.

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)

150 mg

To make up the correct injection volume

use 0.6 ml from one Xolair 150 mg vial.

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

Severe Asthma - 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 for adults and adolescents (12 Years of age and older) with Severe

Asthma

Body weight (kg)

Baseline

IgE

(IU/ml)

>25-

>30- 4

>40- 5

>50- 6

>60- 7

>70- 8

>80- 9

>90-

>125-

30-100

>100-200

>200-300

>300-400

>400-500

>500-600

>600-700

>700-800

>800-900

ADMINISTRATION EVERY 2 WEEKS

SEE TABLE 3

>900-

1000

>1000-

1100

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

subcutaneous injection every 2 weeks for adults and adolescents (12 Years of age and older) with Severe

Asthma

Body weight (kg)

Baseline

IgE

(IU/ml)

>25-

>30- 4

>40-

>50- 6

>60- 7

>70- 8

>80- 9

>90-

>125-

30-100

ADMINISTRATION EVERY 4 WEEKS

SEE TABLE 2

>100-200

>200-300

>300-400

>400-500

>500-600

>600-700

>700-800

>800-900

>900-

1000

>1000-

1100

>1100-

1200

DO NOT ADMINISTER– data is

unavailable for dose recommendation

>1200-

1300

>1300-

1500

Moderate Asthma - Adults and Adolescents (12 years of age and older)

Table 4: ADMINISTRATION EVERY 4 WEEKS Xolair Doses (milligrams) Administered by

Subcutaneous Injection Every 4 Weeks for Adults and Adolescents (12 Years of Age and Older)

with Moderate Asthma

Pre-treatment

Serum IgE

Baseline IgE (IU/ml)

Body weight (kg)

30-60

> 60-70

> 70-90

> 90-150

≥30-100

> 100-200

> 200-300

> 300-400

SEE TABLE 5

> 400-500

> 500-600

Table 5: ADMINISTRATION EVERY 2 WEEKS Xolair Doses (milligrams) Administered

by Subcutaneous Injection Every 2 Weeks for Adults and Adolescents (12 Years of Age and

Older) with Moderate Asthma

Pre-treatment

Serum IgE

(IU/mL)

Baseline IgE (IU/ml)

Body weight (kg)

30-60

> 60-70

> 70-90

> 90-150

≥30-100

> 100-200

SEE TABLE 4

> 200-300

> 300-400

> 400-500

> 500-600

Insufficient Data to Recommend

a DoseDO NOT DOSE

> 600-700

Severe Asthma - Pediatric patients (ages of 6 to <12 years)

Pediatric patients (ages of 6 to <12 years): Initiate dosing according to Table 6.

Table 6: Subcutaneous Xolair Doses Every 2 or 4 Weeks* for Pediatric Patients (ages of 6 to <12

years) with Severe Asthma Who Begin Xolair Treatment.

Pre-treatment

Serum IgE

(IU/mL)

Dosing

Freq.

Body Weight

20-25

>25-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90-125

>125-150

Dose (mg)

30-100

Every 4

weeks

>100-200

>200-300

>300-400

>400-500

>500-600

>600-700

>700-800

Insufficient Data

>800-900

Every 2

weeks

to Recommend a Dose

>900-1000

>1000-1100

>1100-1200

>1200-1300

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 time point, 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 2,3,4,5 and 6).

Chronic spontaneous urticaria (CSU)

Posology

The recommended dose is 300 mg by subcutaneous injection every four weeks.

Prescribers are advised to periodically reassess the need for continued therapy.

Clinical trial experience of long-term treatment beyond 6 months in this indication is limited.

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 omalizumab. 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

In allergic asthma, the safety and efficacy of Xolair in paediatric patients below the age of 6 years

have not been established. No data are available.

In CSU, the safety and efficacy of Xolair in paediatric patients below the age of 12 years have not

been established.The safety and efficacy of Xolair in pediatric patients below the age of 12 have not been

established.

Method of administration

For subcutaneous administration only. Xolair must not be Do not administered by the intravenous or

intramuscular route.

Doses of more than 150 mg (Table 1) should be divided across two or more injection sites.

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 powder and solvent for solution for

injection. Therefore treatment with this formulation is intended to be administered by a healthcare

provider only.

For instructions on reconstitution of the medicinal product 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 listed in section 6.1.

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 even after a long duration of treatment. However, mMost 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. The majority of anaphylactic reactions

occurred within the first 3 doses of Xolair. A history of anaphylaxis unrelated to omalizumab may be a

risk factor for anaphylaxis following Xolair administration. Therefore medicinal products for the treatment

of anaphylactic reactions should always be available for immediate use following administration of

Xolair. If an anaphylactic or other serious allergic reaction occurs, administration of Xolair must be

discontinued immediately and appropriate therapy initiated. Patients should be informed that such

reactions are possible and prompt medical attention should be sought if allergic reactions occur. A history

of anaphylaxis unrelated to omalizumab may be a risk factor for anaphylaxis following Xolair

administration.

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.

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 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 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

Since IgE may be involved in the immunological response to some helminth infections, Xolair may

indirectly reduce the efficacy of medicinal products for the treatment of helminthic or other parasitic

infections (see section 4.4).

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 or

CSU will interact with omalizumab.

Allergic asthma

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.

Chronic spontaneous urticaria (CSU)

In clinical studies in CSU, Xolair was used in conjunction with antihistamines (anti-H1, anti-H2) and

leukotriene receptor antagonists (LTRAs). There was no evidence that the safety of omalizumab was

altered when used with these medicinal products relative to its known safety profile in allergic

asthma. In addition, a population pharmacokinetic analysis showed no relevant effect of H2

antihistamines and LTRAs on omalizumab pharmacokinetics (see section 5.2).

Paediatric population

Clinical studies in CSU included some patients aged 12 to 17 years taking Xolair in conjunction with

antihistamines (anti-H1, anti-H2) and LTRAs. No studies have been performed in children under 12 years.

4.6 Fertility, pregnancy and lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1,000 pregnancy outcomes) based on

pregnancy registry and post-marketing spontaneous reports, indicates no malformative or foeto/neonatal

toxicity. A prospective pregnancy registry study (EXPECT) in 250 pregnant women with asthma exposed

to Xolair showed the prevalence of major congenital anomalies was similar (8.1% vs. 8.9%) between

EXPECT and disease-matched (moderate and severe asthma) patients. The interpretation of data may be

impacted due to methodological limitations of the study, including small sample size and non-randomised

design.

Omalizumab crosses the placental barrier. However, There are limited data from the use of omalizumab in

pregnant women. Aanimal studies do not indicate either direct or indirect harmful effects with respect to

reproductive toxicity (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.

If clinically needed, the use of Xolair may be considered during pregnancy.

Breast-feeding

Immunoglobulins G (IgGs) are present in human milk and therefore it is expected that omalizumab will be

present in human milk. It is unknown whether omalizumab is excreted in human milk. Available data in

non-human primates have shown excretion of omalizumab into milk (see section 5.3). A risk to the

newborns/infants cannot be excluded. Omalizumab should not be given during breast-feeding.

The EXPECT study, with 154 infants who had been exposed to Xolair during pregnancy and through

breast-feeding did not indicate adverse effects on the breast-fed infant. The interpretation of data may be

impacted due to methodological limitations of the study, including small sample size and non-randomised

design.

Given orally, immunoglobulin G proteins undergo intestinal proteolysis and have poor bioavailability. No

effects on the breast-fed newborns/infants are anticipated. Consequently, if clinically needed, the use of

Xolair may be considered during breast-feeding.

Fertility

There are no human fertility data for omalizumab. In specifically-designed non-clinical fertility studies, in

non-human primates 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 a separate non-clinical genotoxicity study.

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

Allergic asthma

Summary of safety profile

During clinical trials in 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 trials in children 6 to <12 years of age, the most commonly

reported adverse reactions were headache, pyrexia and upper abdominal pain. Most of the reactions were

mild or moderate in severity.

Tabulated list of adverse reactions

Table 7 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 (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to

<1/1,000) and very rare (<1/10,000). Reactions reported in the post-marketing setting are listed with

frequency not known (cannot be estimated from the available data).

Table 7: Adverse reactions in allergic asthma

Infections and infestations

Uncommon

Pharyngitis

Rare

Parasitic infection

Blood and lymphatic system disorders

Not known

Idiopathic thrombocytopenia, including severe cases

Immune system disorders

Rare

Anaphylactic reaction, other serious allergic conditions,

anti-omalizumab 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

Rare

Systemic lupus erythematosus (SLE)

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

Chronic spontaneous urticaria (CSU)

Summary of safety profile

The safety and tolerability of omalizumab were investigated with doses of 75 mg, 150 mg and 300 mg

every four weeks in 975 CSU patients, 242 of whom received placebo. Overall, 733 patients were

treated with omalizumab for up to 12 weeks and 490 patients for up to 24 weeks. Of those,

412 patients were treated for up to 12 weeks and 333 patients were treated for up to 24 weeks at the

300 mg dose.

Tabulated list of adverse reactions

A separate table (Table 8) shows the adverse reactions for the CSU indication resulting from

differences in dosages and treatment populations (with significantly different risk factors,

comorbidities, co-medications and ages [e.g. asthma trials included children from 6-12 years of age]).

Table 8 lists the adverse reactions (events occurring in ≥1% of patients in any treatment group and ≥2%

more frequently in any omalizumab treatment group than with placebo (after medical review)) reported

with 300 mg in the three pooled phase III studies. The adverse reactions presented are divided into two

groups: those identified in the 12-week and the 24-week treatment periods.

The adverse reactions are listed by MedDRA system organ class. 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:

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) and not known (cannot be estimated from the available data).

Table 8: Adverse reactions from the pooled CSU safety database (day 1 to week 24) at 300 mg Omalizumab

12-Week

Omalizumab studies 1, 2 and 3 Pooled

Frequency category

Placebo N=242

300 mg N=412

Infections and infestations

Sinusitis

5 (2.1%)

20 (4.9%)

Common

Nervous system disorders

Headache

7 (2.9%)

25 (6.1%)

Common

Musculoskeletal and connective tissue disorders

Arthralgia

1 (0.4%)

12 (2.9%)

Common

General disorder and administration site conditions

Injection site reaction*

2 (0.8%)

11 (2.7%)

Common

24-Week

Omalizumab studies 1 and 3 Pooled

Frequency category

Placebo N=163

300 mg N=333

Infections and infestations

Upper respiratory tract

infection

5 (3.1%)

19 (5.7%)

Common

* Despite not showing a 2% difference to placebo, injection site reactions were included as all cases

were assessed causally related to study treatment.

Description of selected adverse reactions 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 below.

Immune system disorders

For further information, see section 4.4.

Anaphylaxis

Anaphylactic reactions were rare in clinical trials. However, post-marketing data following a

cumulative search in the safety database retrieved a total of 898 anaphylaxis cases. Based on an

estimated exposure of 566,923 patient treatment years, this results in a reporting rate of approximately

0.20%.

Arterial thromboembolic events (ATE)

In controlled clinical trials and during interim analyses of an observational study, a numerical

imbalance of ATE was observed. The definition of the composite endpoint ATE included stroke, transient

ischaemic 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 patient 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 0.91-1.91). In a separate analysis of pooled clinical trials,

which included all randomised double-blind, placebo-controlled clinical trials lasting 8 or more weeks, the

rate of ATE per 1,000 patient years was 2.69 (5/1,856 patient years) for Xolair-treated patients and

2.38 (4/1,680 patient years) for placebo patients (rate ratio 1.13, 95% confidence interval 0.24-5.71).

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, including severe cases, have been reported in the post-marketing setting.

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 section 4.4).

Systemic lupus erythematosus

Clinical trial and post-marketing cases of systemic lupus erythematosus (SLE) have been reported in

patients with moderate to severe asthma and CSU. The pathogenesis of SLE is not well understood.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse

events should be reported to the Ministry of Health according to the National Regulation by using an

online form

ov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

http://forms.g

https://sideeffects.health.gov.il/

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for obstructive airway diseases, 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.

Allergic asthma

Mechanism of action

Omalizumab binds to IgE and prevents binding of IgE to Fc

RI (high-affinity IgE receptor) on

basophils and mast cells, 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 Fc

RI receptors on basophils.

Pharmacodynamic effects

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 allergic asthma patients, 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.

Chronic spontaneous urticaria (CSU)

Mechanism of action

Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcεRI) on cells

down-regulate. It is not entirely understood how this results in an improvement of CSU symptoms.

Pharmacodynamic effect

In clinical studies in CSU 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. After discontinuation of Xolair, free IgE

levels increased towards pre-treatment levels over a 16-week treatment-free follow-up period

Clinical efficacy and safety in allergic asthma

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 (FEV

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 9 includes

results in the study 1 population.

Table 9: Results of study 1

Whole study 1

population

Xolair

N=209

Placebo

N=210

Asthma exacerbations

Rate per 28-week period

0.74

0.92

% reduction, p-value for rate ratio

19.4%, p = 0.153

Severe asthma exacerbations

Rate per 28-week period

0.24

0.48

% reduction, p-value for rate ratio

50.1%, p = 0.002

Emergency visits

Rate per 28-week period

0.24

0.43

% reduction, p-value for rate ratio

43.9%, p = 0.038

Physician’s overall assessment

% responders*

60.5%

42.8%

p-value**

<0.001

AQL improvement

% of patients ≥0.5 improvement

60.8%

47.8%

p-value

0.008

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.

Clinical efficacy and safety in chronic spontaneous urticaria (CSU)

The efficacy and safety of Xolair were demonstrated in two randomised, placebo-controlled phase III

studies (study 1 and 2) in patients with CSU who remained symptomatic despite H1 antihistamine

therapy at the approved dose. A third study (study 3) primarily evaluated the safety of Xolair in

patients with CSU who remained symptomatic despite treatment with H1 antihistamines at up to four

times the approved dose and H2 antihistamine and/or LTRA treatment. The three studies enrolled

975 patients aged between 12 and 75 years (mean age 42.3 years; 39 patients 12-17 years, 54 patients

≥65 years; 259 males and 716 females). All patients were required to have inadequate symptom

control, as assessed by a weekly urticaria activity score (UAS7, range 0-42) of ≥16, and a weekly itch

severity score (which is a component of the UAS7; range 0-21) of ≥8 for the 7 days prior to

randomisation, despite having used an antihistamine for at least 2 weeks beforehand.

In studies 1 and 2, patients had a mean weekly itch severity score of between 13.7 and 14.5 at baseline

and a mean UAS7 score of 29.5 and 31.7 respectively. Patients in safety study 3 had a mean weekly

itch severity score of 13.8 and a mean UAS7 score of 31.2 at baseline. Across all three studies, patients

reported receiving on average 4 to 6 medications (including H1 antihistamines) for CSU symptoms prior

to study enrollment. Patients received Xolair at 75 mg, 150 mg or 300 mg or placebo by subcutaneous

injection every 4 weeks for 24 and 12 weeks in studies 1 and 2, respectively, and 300 mg or placebo by

subcutaneous injection every 4 weeks for 24 weeks in study 3. All studies had a 16-week treatment-free

follow-up period.

The primary endpoint was the change from baseline to week 12 in weekly itch severity score.

Omalizumab at 300 mg reduced the weekly itch severity score by 8.55 to 9.77 (p <0.0001) compared

to a reduction of 3.63 to 5.14 for placebo (see Table 10). Statistically significant results were further

observed in the responder rates for UAS7≤6 (at week 12) which were higher for the 300 mg treatment

groups, ranging from 52-66% (p<0.0001) compared to 11-19% for the placebo groups, and complete

response (UAS7=0) was achieved by 34-44% (p<0.0001) of patients treated with 300 mg compared to

5-9% of patients in the placebo groups. Patients in the 300 mg treatment groups achieved the highest

mean proportion of angioedema-free days from week 4 to week 12, (91.0-96.1%; p<0.001) compared

to the placebo groups (88.1-89.2%). Mean change from baseline to week 12 in the overall DLQI for

the 300 mg treatment groups was greater (p<0.001) than for placebo showing an improvement ranging

from 9.7-10.3 points compared to 5.1-6.1 points for the corresponding placebo groups.

Table 10: Change from baseline to week 12 in weekly itch severity score, studies 1, 2 and 3

(mITT population*)

Placebo

Omalizumab

300 mg

Study 1

Mean (SD)

−3.63 (5.22)

−9.40 (5.73)

Difference in LS means vs. placebo

−5.80

95% CI for difference

−7.49,−4.10

P-value vs. placebo

<0.0001

Study 2

Mean (SD)

−5.14 (5.58)

−9.77 (5.95)

Difference in LS means vs. placebo

−4.81

95% CI for difference

−6.49,−3.13

P-value vs. placebo

<0.0001

Study 3

Mean (SD)

−4.01 (5.87)

−8.55 (6.01)

Difference in LS means vs. placebo

-4.52

95% CI for difference

−5.97, −3.08

P-value vs. placebo

<0.0001

*Modified intent-to-treat (mITT) population: included all patients who were randomised and received

at least one dose of study medication.

BOCF (Baseline Observation Carried Forward) was used to impute missing data.

The LS mean was estimated using an ANCOVA model. The strata were baseline weekly itch

severity score (<13 vs. ≥13) and baseline weight (<80 kg vs. ≥80 kg).

p-value is derived from ANCOVA t-test.

Figure 1 shows the mean weekly itch severity score over time in study 1. The mean weekly itch

severity scores significantly decreased with a maximum effect around week 12 that was sustained

over the 24-week treatment period. The results were similar in study 3.

In all three studies the mean weekly itch severity score 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.

Figure 1: Mean weekly itch severity score over time, study 1 (mITT population)

BOCF=baseline observation carried forward; mITT=modified intention-to-treat population

Efficacy after 24 weeks of treatment

The magnitude of the efficacy outcomes observed at week 24 of treatment was comparable to that

observed at week 12:

For 300 mg, in studies 1 and 3, the mean decrease from baseline in weekly itch severity score was 9.8

and 8.6, the proportion of patients with UAS7≤6 was 61.7% and 55.6%, and the proportion of patients

with complete response (UAS7=0) was 48.1% and 42.5%, respectively, (all p<0.0001, when

compared to placebo).

There is limited clinical experience in re-treatment of patients with omalizumab.

Clinical trial data on adolescents (12 to 17 years) included a total of 39 patients, of whom 11 received

the 300 mg dose. Results for the 300 mg are available for 9 patients at week 12 and 6 patients at

week 24, and show a similar magnitude of response to omalizumab treatment compared to the adult

population. Mean change from baseline in weekly itch severity score showed a reduction of 8.25 at

week 12 and of 8.95 at week 24. The responder rates were: 33% at week 12 and 67% at week 24 for

UAS7=0, and 56% at week 12 and 67% at week 24 for UAS7≤6.

5.2 Pharmacokinetic properties

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

asthma as well as in adult and adolescent patients with CSU. The general pharmacokinetic

characteristics of omalizumab are similar in these populations.

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 or CSU,

omalizumab was absorbed slowly, reaching peak serum concentrations after an average of 6-8 days. In

patients with asthma, 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.

The pharmacokinetics of omalizumab are linear at doses greater than 0.5 mg/kg. Following doses of

75 mg, 150 mg or 300 mg every 4 weeks in patients with CSU, trough serum concentrations of

omalizumab increased proportionally with the dose level.

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

in vivo

Based on population pharmacokinetics, distribution of omalizumab was similar in patients with

allergic asthma and patients with CSU. The apparent volume of distribution in patients with asthma

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. Doubling of body weight approximately doubled apparent clearance.

In CSU patients, based on population pharmacokinetic simulations, omalizumab serum elimination

half-life at steady state averaged 24 days and apparent clearance at steady state for a patient of 80 kg

weight was 3.0 ml/kg/day.

Characteristics in patient populations

Patients with asthma

The population pharmacokinetics of omalizumab were analysed to evaluate the

effects of demographic characteristics. Analyses of these limited data suggest that no dose

adjustments are necessary in patients with asthma for age ( 126-76 years), race/ethnicity, gender or body

mass index (see section 4.2).

Patients with CSU

The effects of demographic characteristics and other factors on omalizumab

exposure were evaluated based on population pharmacokinetics. In addition, covariate effects were

evaluated by analysing the relationship between omalizumab concentrations and clinical responses.

These analyses suggest that no dose adjustments are necessary in patients with CSU for age

(12-75 years), race/ethnicity, gender, body weight, body mass index, baseline IgE, anti-Fc

autoantibodies or concomitant use of H2 antihistamines or LTRAs.

Renal and hepatic impairment

There are no pharmacokinetic or pharmacodynamic data in allergic asthma or CSU patients with renal

or hepatic impairment (see sections 4.2 and 4.4).

5.3 Preclinical safety data

The safety of omalizumab has been studied in the cynomolgus monkey, since omalizumab binds to

cynomolgus and human IgE with similar affinity. Antibodies to omalizumab were detected in some

monkeys following repeated subcutaneous or intravenous administration. However, no apparent

toxicity, such as immune complex-mediated disease or complement-dependent cytotoxicity, was seen.

There was no evidence of an anaphylactic response due to mast-cell degranulation in cynomolgus

monkeys.

Chronic administration of omalizumab at dose levels of up to 250 mg/kg (at least 14 times the highest

recommended clinical dose in mg/kg according to the recommended dosing table) 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.

Formal carcinogenicity studies have not been conducted with omalizumab.

In reproduction studies in cynomolgus monkeys, subcutaneous doses up to 75 mg/kg per week (at least 8

times the highest recommended clinical dose in mg/kg over a 4 week period) 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.

Omalizumab is excreted in breast milk in cynomolgus monkeys. Milk levels of omalizumab were 0.15%

of the maternal serum concentration.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder

Sucrose 108mg/1.2mL

L-histidine hydrochloride monohydrate

L-histidine

Polysorbate 20

Solvent

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

6.3 Shelf life

The expiry date of the product is printed on the package materials.

After reconstitution

The chemical and physical stability of the reconstituted medicinal product have been demonstrated for 8

hours at 2°C to 8°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 2 hours at

25°C.

6.4 Special precautions for storage

Store in a refrigerator (2

C - 8

Do not freeze.

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

6.5 Nature and contents of container

Powder vial: Clear, colourless type I glass vial with a chlorobutyl rubber stopper and blue flip-off seal.

Solvent ampoule: Clear, colourless type I glass ampoule containing 2 ml water for injections.

Packs containing 1 vial of powder and 1 ampoule of water for injections, respectively.

6.6 Special precautions for disposal and other handling

Xolair 150 mg powder for solution for injection is supplied in a single-use vial.

From a microbiological point of view, the medicinal product should be used immediately after

reconstitution (see section 6.3).

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 to slightly opalescent, colorless to pale

brownish-yellow 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

product from the vial before expelling any air or excess solution from the syringe in order to obtain the 1.2

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

requirements.

7. Manufacturer:

Novartis Pharma Stein AG, Stein

Switzerland

For: Novartis Pharma AG, Basel, Switzerland.

8. Registration number:

132 61 31124.

9. Registration Holder:

Novartis Israel Ltd.

P.O.B 7126, Tel Aviv

Revised in August 2020.

INFORMATION FOR THE HEALTHCARE PROFESSIONAL

The following information is intended for healthcare professionals only:

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 to slightly opalescent, colourless to

pale brownish-yellow 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

product from the vial before expelling any air or excess solution from the syringe in order to obtain the

1.2 ml.

To prepare Xolair 150 mg vials for subcutaneous administration, please adhere to the following

instructions:

1. Draw 1.4 ml of water for injections from the ampoule into a 3 ml syringe equipped with 1– inch a large-

bore 18-gauge needle.

2. With the vial placed upright on a flat surface, using standard aseptic technique insert the needle and

transfer the water for injections into the vial containing the lyophilised powder using standard aseptic

techniques, directing the water for injections directly on to the powder.

3. Keeping the vial in an upright position, vigorously swirl it (do not shake) for approximately

1 minute to evenly wet the powder.

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 to lightly opalescent, colourless to pale brownish-yellow. Do not use if

solid particles are present.

5. Invert the vial for at least 15 seconds in order to allow the solution to drain towards the stopper.

Using a new 3-ml syringe equipped with 1-inch, large-bore, 18-gauge needle, insert the needle into

the inverted vial. Keeping the vial inverted position the needle tip at the very bottom of the

solution in the vial 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, it may take 5-10 seconds to administer the solution by subcutaneous injection.

The vial delivers 1.2 ml (150 mg) of Xolair. For a 75 mg dose, draw up 0.6 ml into the syringe

and discard the remaining solution.

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

the lower abdomen (but

not the area 5 centimetres around the navel),

or the thigh.

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