Omalizumab in Patients with Convincing IgE ( Immunoglobulin E ) Mediated Asthma - Guidelines for the Prescribing and Administration of

Publication: 01/04/2008  --
Last review: 05/10/2017  
Next review: 01/10/2020  
Clinical Guideline
CURRENT 
ID: 1252 
Approved By: LTHT Drug and Therapeutics Committee 
Copyright© Leeds Teaching Hospitals NHS Trust 2017  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines for the Prescribing and Administration of Omalizumab in Patients with Convincing IgE (Immunoglobulin E) Mediated Asthma

Introduction1,2,3 

Asthma is a chronic inflammatory disorder of the airways. It often has an allergic component resulting in over-production of human immunoglobulin E (IgE) in response to environmental allergens e.g. pollen, house dust mite. IgE binds to cell membrane receptors resulting in the release of inflammatory mediators.

Omalizumab (Xolair, Novartis®) is a recombinant humanised monoclonal antibody that selectively binds to (IgE) forming an omalizumab-IgE complex. This prevents IgE binding to receptor sites on mast cells and basophils. Removal of free IgE also results in down-regulation of these receptors. Both these effects are reversible on discontinuation of the drug.

Omalizumab has been shown to reduce the rate and severity of asthma exacerbations and to improve lung function and quality of life. Treatment should only be considered for patients with convincing IgE (immunoglobulin E) mediated asthma.1

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Indication2,3

Adults and adolescents (12 years of age and older)
Omalizumab is indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and who have reduced lung function (forced expiratory volume at one second - [FEV1] < 80%) as well as frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist.

Children (6 to <12 years of age) 
Omalizumab is indicated as add-on therapy to improve asthma control in patients with severe persistent allergic asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and frequent daytime symptoms or night-time awakenings and who have had multiple documented severe asthma exacerbations despite daily high-dose inhaled corticosteroids, plus a long-acting inhaled beta2-agonist.

Note: This guideline does NOT cover the use of omalizumab as an add‑on therapy for treating severe chronic spontaneous urticaria in adults and young people aged 12 years and over, who have had an inadequate response to H1 antihistamine treatment. Please contact immunology for advice/guidance. 

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National Institute for Health and Care Excellence (NICE) technology Appraisal Guidance 2781

Omalizumab is recommended as an option for treating severe persistent confirmed allergic IgE-mediated asthma as an add-on to optimised standard therapy in people aged 6 years and older:

  • who need continuous or frequent treatment with oral corticosteroids (defined as 4 or more courses in the previous year), and
  • Only if the manufacturer makes omalizumab available with the discount agreed in the patient access scheme.

Optimised standard therapy is defined as a full trial of and, if tolerated, documented compliance with inhaled high-dose corticosteroids, long-acting beta2 agonists, leukotriene receptor antagonists, theophyllines, oral corticosteroids, and smoking cessation if clinically appropriate.

In addition, existing people currently receiving omalizumab whose disease does not meet the current NICE criteria are allowed to continue treatment until they and their clinician considers it appropriate to stop.

Omalizumab add-on therapy should only be initiated if the patient with severe persistent allergic asthma has:

  • A positive skin test or in vitro reactivity to a perennial aeroallergen
  • Reduced lung function (forced expiratory volume at one second - [FEV1])
    • less than 80% (in adults and adolescents)
  • Frequent daytime symptoms or night time awakenings
  • Multiple documented severe exacerbations despite daily high dose inhaled corticosteroids plus a long-acting inhaled beta2 agonist

Omalizumab add-on therapy should be initiated and monitored by a physician experienced in the diagnosis and treatment of severe persistent asthma.

16 weeks after the start of omalizumab physicians should assess how effective the treatment is and should continue omalizumab only in patients whose asthma has markedly improved. Response to treatment should be defined on the basis of a full clinical assessment comprising: degree of asthma control, quality of life, control of exacerbations, avoidance of unscheduled healthcare utilisation; spirometry and peak expiratory flow measures and a global evaluation of treatment effectiveness, as assessed by the physician.

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Patient Access Scheme (PAS)

The manufacturer of omalizumab has agreed a PAS with the department of health which makes omalizumab available with a discount applied to all invoices.

The size of the discount is commercial in confidence

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Patient Selection

All patients (aged 6 years and over) must meet the NICE criteria to be eligible for omalizumab treatment:

  • Their body weight and baseline IgE level must allow a dose to be calculated using the Dose Determination Charts in the manufacturer’s Summary of Product Characteristics (SPC).
    • Body weight between 20 and 150kg
    • IgE between 30 and 1500(IU/ml) will be considered
  • 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 due to likelihood of experiencing less benefit.
  • Allergic component to asthma will have been confirmed by a positive skin prick test, the wheal will be greater than 3mm than the negative control, or a specific IgE test.
  • Appropriate allergen avoidance measures should have been carried out.
  • An assessment of patient compliance with their existing medication should be made, including an assessment of their inhaler technique.

Only patients who are compliant with their other medication and allergen avoidance will be considered for omalizumab.

All patients being considered for omalizumab treatment will be put through a difficult asthma protocol to confirm the diagnosis of asthma and to ensure that no other contributory factors have been overlooked.  See Difficult Asthma Investigations (Appendix 1).

This may include (where appropriate):

  1. Specialist assessment
  2. Specialist nurse assessment
  3. Physiotherapy assessment
  4. Psychiatric/psychological assessment
  5. Lung Function Testing including transfer factor, exhaled nitric oxide (FENO) and airway hyper-responsiveness testing)
  6. Immunological testing (immunoglobulin levels, IgE, specific IgEs, or skin prick tests)
  7. Routine blood testing
  8. HRCT Thorax
  9. Cardiopulmonary Exercise Testing (CPET)
  10. Sleep Study
  11. Echocardiogram

Not all of the above are available or carried out in children.

In addition to the above the following data will be documented (previous four months)

  1. Number of severe exacerbations
  2. Number of Emergency Room visits
  3. Number of GP visits
  4. Night time awakenings
  5. Symptom assessment (cough, shortness of breath, wheeze, chest tightness)
  6. Daily dose rescue medication (beta agonist)
  7. Daily dose oral corticosteroid
  8. Daily dose inhaled corticosteroid
  9. Days off work/education in past month
  10. Asthma Quality of life questionnaire (AQLQ) score (Juniper asthma QOL: >0.5 change improvement)
  11. FEV1
  12. Asthma control questionnaire (ACQ) score (>0.5 change improvement)
  13. EQ-5D questionnaire

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Contra-indications2

  • Hypersensitivity to the active substance or to any of the excipients
  • Pregnancy

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Cautions2

Caution should be exercised when administering omalizumab in patients with autoimmune diseases, immune complex-mediated conditions, or pre-existing renal or hepatic impairment, due to a lack of data in these populations.

Patients at chronic high risk of helminth infection may be at increased risk of helminth infections, although the course, severity, and response to treatment of infection were unaltered in studies.

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Adverse Effects2

During clinical trials in adult and adolescent patients 12 years of age and older, the most commonly reported adverse reactions were injection site reactions, including injection site pain, swelling, erythema and pruritus, and headaches.

In clinical trials in patients 6 to <12 years of age, the most commonly reported adverse reactions suspected of being related to the medicinal product were headache, pyrexia and upper abdominal pain. Most of the reactions were mild or moderate in severity.

In clinical studies very common (≥1/10) and common (≥1/100 to <1/10) adverse effects reported included:

Nervous system disorders

Common

Headache*

Gastrointestinal disorders

Common

Abdominal pain upper**

General disorders and administration site conditions

Very common

Pyrexia**

Common

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

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

Anaphylaxis (Rare ≥1/10,000 to <1/1,000)
Anaphylaxis has presented as bronchospasm (Uncommon), hypotension, syncope, urticaria, and/or angioedema of the throat or tongue. Hypersensitivity reactions can also occur immediately following treatment with omalizumab or sometimes more than 24 hours after the first injection3.

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%.

Discuss the risk of anaphylaxis with patients prior to administration of omalizumab (see notes below) 

Parasitic infections (Rare ≥1/10,000 to <1/1,000) 
In patients at chronic high risk of helminth infection, a placebo-controlled trial showed a slight numerical increase in infection rate with omalizumab that was not statistically significant. The course, severity, and response to treatment of infections were unaltered.

Systemic lupus erythematosus (Rare ≥1/10,000 to <1/1,000)
Clinical trial and post-marketing cases of systemic lupus erythematosus (SLE) have been reported in patients with moderate to severe asthma and Chronic Spontaneous Urticaria (CSU). The pathogenesis of SLE is not well understood.

Arterial thromboembolic events (ATE) (Incidence not known)
In controlled clinical trials and an on-going observational study, a numerical imbalance of ATEs was observed. ATE included stroke, transient ischaemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause).

Churg-Strauss syndrome (Incidence not known)
Churg-Strauss syndrome can present as eosinophilia, vasculitic rash, cardiac complications, worsening pulmonary symptoms, or peripheral neuropathy. This has occurred rarely in patients given omalizumab; the reaction is usually associated with the reduction of adjunctive oral corticosteroid therapy.

Platelets (Incidence not known) 
In clinical trials few patients had platelet counts below the lower limit of the normal laboratory range, but these were not associated with bleeding episodes or a decrease in haemoglobin. No pattern of persistent decrease in platelet counts, as observed in non-human primates, has been reported in humans (patients above 6 years of age), even though isolated cases of idiopathic thrombocytopenia have been reported in the post-marketing setting.

For further information on adverse reactions please see the manufacturers SPC for Omalizumab (Xolair), Novartis®. Available at: http://emc.medicines.org.uk/

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Pregnancy, breast feeding and Fertility2 

Pregnancy
There are limited data from the use of omalizumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. 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. Omalizumab (Xolair) should not be used during pregnancy unless clearly necessary.

Breast-feeding
It is unknown whether omalizumab is excreted in human milk. Available data in non-human primates have shown excretion of omalizumab into milk. A risk to the newborns/infants cannot be excluded. Omalizumab should not be given 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 separate non-clinical genotoxicity studies.

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Dosing and Administration of omalizumab

Omalizumab must be prescribed on the ‘Omalizumab Subcutaneous Injection Administration Record’ (Prescription Chart Ref No: 08/002; Appendix 2). Ensure that all relevant information is recorded on the chart (i.e. weight).

All adult patient doses will be administered in the Respiratory Day Case Unit on Ward 12 at SJUH.

All children will be admitted to the paediatric ward (L49) under the care of a Paediatric Respiratory Physician for administration of the injections. 

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Dose of omalizumab2

  • The usual dose is 75-600mg of omalizumab in 1 to 4 injections every two to four weeks (maximum dose 600mg every 2 weeks).
  • Use the following tables (1 & 2) to determine the required dose, based on baseline IgE level, bodyweight (ensure bodyweight is updated on each visit) and frequency of doses.
  • Doses should be adjusted for significant changes in body weight; this should be monitored on each visit.

Dose determination charts in adults, adolescents and children (6 to <12 years of age)2

Table 1: Omalizumab doses administered by subcutaneous injection every 4 weeks.

 

Body weight (kg)

Baseline IgE (IU/ml)

≥20-25

>25-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90-125

>125-150

≥30-100

75

75

75

150

150

150

150

150

300

300

>100-200

150

150

150

300

300

300

300

300

450

600

>200-300

150

150

225

300

300

450

450

450

600

 

>300-400

225

225

300

450

450

450

600

600

 

 

>400-500

225

300

450

450

600

600

 

 

 

 

>500-600

300

300

450

600

600

 

 

 

 

 

>600-700

300

 

450

600

 

 

 

 

 

 

>700-800

 

 

 

 

 

 

 

 

 

 

>800-900

 

 

 

 

ADMINISTRATION EVERY TWO WEEKS

SEE TABLE 2

 

>900-1000

 

 

 

 

 

>1000-1100

 

 

 

 

 

 

 

 

 

 

 

Table 2: Omalizumab doses administered by subcutaneous injection every 2 weeks.

 

Body weight (kg)

Baseline IgE (IU/ml)

≥20-25

>25-30

>30-40

>40-50

>50-60

>60-70

>70-80

>80-90

>90-125

>125-150

≥30-100

 

 

 

 

 

 

 

 

 

 

>100-200

 

ADMINISTRATION EVERY FOUR WEEKS

SEE TABLE 1

 

 

 

>200-300

 

 

 

375

>300-400

 

 

 

 

 

 

 

 

450

525

>400-500

 

 

 

 

 

 

375

375

525

600

>500-600

 

 

 

 

 

375

450

450

600

 

>600-700

 

225

 

 

375

450

450

525

 

 

>700-800

225

225

300

375

450

450

525

600

 

 

>800-900

225

225

300

375

450

525

600

 

 

 

>900-1000

225

300

375

450

525

600

 

 

 

 

>1000-1100

225

300

375

450

600

 

DO NOT ADMINISTER -Data unavailable for dose recommendation

>1100-1200

300

300

450

525

600

 

>1200-1300

300

375

450

525

 

 

>1300-1500

300

375

525

600

 

 

 

 

 

 

Conversion from dose to number of syringes, number of injections and total injection volume for each administration2

  • One syringe of 0.5ml solution contains 75mg of omalizumab.
  • One syringe of 1ml solution contains 150mg of omalizumab.

Dose (mg)

 

Number of syringes

Number of injections 

Total injection volume (ml)

75 mg

150 mg

75

1

0

1

0.5

150

0

1

1

1.0

225

1

1

2

1.5

300

0

2

2

2.0

375

1

2

3

2.5

450

0

3

3

3.0

525

1

3

4

3.5

600

0

4

4

4.0Bottom of Form

Prior to administration

At each visit the patients overall asthma control and response to omalizumab will be assessed (see Appendix 3 & 4). Ensure pre-observation checks have been performed before administration with records of base line observations (Blood Pressure, Pulse, Temperature, Respiratory Rate and SpO2) on the Biologics record sheet (Appendix 3).

The potential possibility of anaphylaxis should be discussed with all patients and carers prior to administration.

In the case, you are required to issue the patient with an anaphylaxis kit (adrenaline auto-injector EpiPens® or Emarade®, stat dose of prednisolone 50mg and course of antihistamines), they should be given clear verbal and written instruction on what to do should anaphylaxis occur.

Administration of omalizumab

For all patients, omalizumab will be administered in hospital on the appropriate ward/clinic. Beforehand patients will receive education on the role and rationale for treatment and the potential side effects.

Administration of omalizumab must be performed according to the package insert supplied with each syringe of omalizumab.

Prior to completion of the injection, avoid contact with the device activation clips to keep from prematurely covering the needle with the needle guard. 

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Equipment required for administration of the subcutaneous injection

  • One, two, three or four prefilled syringes of omalizumab depending on prescription.
  • Alcohol swab
  • Plaster if required
  • Sharps container
  • Anaphylaxis kit (only for patients with a history of anaphylaxis)

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Patient monitoring following administration

  • Observe patient for potential adverse effects
    • In case of any adverse reaction ensure the physician is consulted straight away.
  • Observation of the patient will take place for 4 hours post the first 2 injections.
  • After the 3rd dose patients are monitored for 1 hour, this will continues for subsequent doses until the 16 week trial period has finished.
  • After the 16 week assessment period patients are then observed 30 minutes after injections.
  • Post injection pulse, respiratory rate and blood pressure are recorded half hourly for one hour, then hourly until discharge or depending on clinical condition.
  • A formal 16 week assessment of the response to treatment with omalizumab by a physician will be carried out (Appendix 3).
    • If the patient’s response is assessed as good or excellent, they should be allowed to continue with treatment.
    • The physician was able to take into account Peak Expiratory Flow (PEF), day and night time symptoms, rescue medication use, spirometry and exacerbations.
    • If the patient’s response is assessed as worse, no response, or poor they should stop treatment. 

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Provenance

Record: 1252
Objective:
  • Ensure appropriate patient selection for omalizumab
  • Ensure appropriate treatment and monitoring of omalizumab
Clinical condition:

Severe persistent allergic asthma

Target patient group: Asthma patients
Target professional group(s): Pharmacists
Secondary Care Doctors
Secondary Care Nurses
Adapted from:

Evidence base

  1. National Institute for Health and Clinical Excellence (2013).  NICE technology appraisal guidance 278. Omalizumab for treating severe persistent allergic asthma (review of technology appraisal guidance 133 and 201). https://www.nice.org.uk/guidance/ta278 (Accessed 07/07/2017. Last updated in 2013).
  2. Summary of Product Characteristics. Electronic Medicines Compendium. Datapharm Communications Ltd. (Xolair®, Novartis®).  http://emc.medicines.org.uk/ (Accessed 07/07/2017. Last updated on the eMC: 26/09/2016).
  3. JOINT FORMULARY COMMITTEE, 2017.  British National Formulary. 72. London: BMJ Group and Pharmaceutical Press. Online version available at : https://www.bnf.org/ (Accessed 18/07/2017).

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Approved By

LTHT Drug and Therapeutics Committee

Document history

LHP version 1.0

Related information

Appendix 1 - DIFFICULT ASTHMA INVESTIGATIONS 

 

Level 1 investigations

Level 2 investigations

Further investigations

Routinely undertaken in all patients

Undertaken in patients where initial assessment and level 1 investigations have not resulted in control of therapy

Investigations undertaken in selected individuals where clinically indicated

Lung physiology

Spirometry

Full lung function including DLCO
Reversibility +/- bronchial provocation studies

CPEX
Sleep study

Imaging

CXR

HRCT thorax

Echo
DEXA bone scan
CT sinuses

Blood tests

FBC
U+E / LFT / Calcium
Total IgE
IgE to inhaled allergen mix

Specific IgEs
Aspergillus IgE
Aspergillus IgG
Immunoglobulins
Vasculitis screen
Random cortisol

Functional antibodies
Serum ACE
TFTs
Short syncathen

Airways inflammation

FeNO

 

Sputum cytology

Microbiology

Sputum MC+S

Sputum AAFB culture

 

Asthma scores

ACQ

EQ-5D

 

Prior to commencing omalizumab, patients should have undergone Level 1 and Level 2 investigations, unless clinically contraindicated.

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Appendix 2

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Appendix 3

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Appendix 4

Assessing Response to treatment with Omalizumab

All patients receiving omalizumab will be assessed formally by a physician at 16 weeks.

The physician’s overall assessment will include: 

  1. Number of severe exacerbations
  2. Number of Emergency Room visits
  3. Number of GP visits
  4. Night time awakenings
  5. Symptom assessment (cough, shortness of breath, wheeze, chest tightness)
  6. Daily dose rescue medication (beta agonist)
  7. Daily dose oral corticosteroid
  8. Daily dose inhaled corticosteroid
  9. Days off work/education in past month
  10. Asthma Quality of life questionnaire (AQLQ) (Juniper asthma QOL: >0.5 change improvement)
  11. FEV1
  12. Asthma Control Questionnaire (ACQ) (Minimal change >0.5)
  13. EQ-5D questionnaire

On the basis of this the physician will grade the response to treatment

1. Excellent (complete control)
2. Good  (marked improvement)
3. Poor  (no appreciable change)
4. Worsening of Asthma

Continuation of treatment will be recommended if the patient has had an excellent or good response to omalizumab.

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Equity and Diversity

The Leeds Teaching Hospitals NHS Trust is committed to ensuring that the way that we provide services and the way we recruit and treat staff reflects individual needs, promotes equality and does not discriminate unfairly against any particular individual or group.