Xolair Prefilled Syringe

Uses

Xolair Prefilled Syringe is a recombinant DNA-derived humanized IgG1κ monoclonal antibody that selectively binds to human immunoglobulin E (IgE). The antibody has a molecular weight of approximately 149 kiloDaltons. Xolair Prefilled Syringe is produced by a Chinese hamster ovary cell suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product.

Asthma: Xolair Prefilled Syringe is used for patients 6 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 Prefilled Syringe has been shown to decrease the incidence of asthma exacerbations in these patients.

Chronic Idiopathic Urticaria (CIU): Xolair Prefilled Syringe is used for the treatment of adults and adolescents 12 years of age and older with chronic idiopathic urticaria who remain symptomatic despite H1 antihistamine treatment.

Xolair Prefilled Syringe is also used to associated treatment for these conditions: Chronic Idiopathic Urticaria, Moderate Asthma, Severe Asthma

How Xolair Prefilled Syringe works

When an environmental allergen first enters the body, is taken up by antigen-presenting cells (APCs). It is then processed, and presented to T and B immune cells. This is followed by the activation of B-lymphocyte and production of allergen-specific IgE. This IgE is then released by plasma cells (converted B lymphocytes) and is therefore available to bind to IgE receptors on several other cells .

IgE binds to high-affinity (Fc€RI) and low-affinity (Fc€RII) receptors on multiple cells of the immune system. Following subsequent antigen exposure, cross-linking of the antigen occurs by several Fc€RI-bound IgE molecules on the surface of both basophils and mast cells. This leads to the activation of mast cells and histamine release, producing a wheal and other symptoms of urticaria .

The following are explanations of the mechanism of action for both indications of this drug:

Asthma

Xolair Prefilled Syringe inhibits the binding of IgE to the high-affinity IgE receptor (FcεRI) on the surface of both mast cells and basophils. The reduction in surface-bound IgE on FcεRI-bearing cells limits the degree of release of mediators of the typical allergic response. Treatment with omalizumab also reduces the number of FcεRI receptors on basophils in atopic patients .

Xolair Prefilled Syringe binds to free IgE with a higher affinity than IgE itself binds to the high-affinity Fc€RI receptors found on basophils. Therefore, it decreases the availability of free IgE for binding . Xolair Prefilled Syringe by itself does not bind to the Fc€RI receptors, nor does the drug bind to receptor-bound IgE. These binding characteristics allow omalizumab to neutralize the typical IgE-mediated responses without causing the degranulation of basophils or cross-linking with basophil-bound IgE .

Chronic Idiopathic Urticaria Xolair Prefilled Syringe binds to IgE and decreases free IgE levels. Subsequently, IgE receptors (FcεRI) on cells are down-regulated. The mechanism by which these effects of omalizumab result in an improvement of CIU symptoms is unclear.

Dosage

Xolair Prefilled Syringe dosage

Subcutaneous-

Poorly controlled, moderate to severe asthma:

• Adult: Doses (mg) and dosing frequency are based on pre-treatment serum IgE levels (IU/mL) and body wt (kg) as follows: ≥30-100 IU/mL: 150 mg (30-90 kg); 300 mg (>90-150 kg). >100-200 IU/mL: 300 mg (30-90 kg). >200-300 IU/mL: 300 mg (30-60 kg). All doses to be taken every 4 wk. >100-200 IU/mL: 225 mg (>90-150 kg). >200-300 IU/mL: 225 mg (>60-90 kg); 300 mg (>90-150 kg). >300-400 IU/mL: 225 mg (30-70 kg); 300 mg (>70-90 kg). >400-500 IU/mL: 300 mg (30-70 kg); 375 mg (>70-90 kg). >500-600 IU/mL: 300 mg (30-60 kg); 375 mg (>60-70 kg). 375 mg (30-60 kg). All doses to be taken every 2 wk. Doses no more than 150 mg should be admin at 1 inj site.
• Child: ≥12 yr Same as adult dose.

Chronic idiopathic urticaria:

• Adult: 150 or 300 mg every 4 wk.
• Child: ≥12 yr Same as adult dose.

Xolair Prefilled Syringe is a sterile, white, preservative free, lyophilized powder contained in a single use vial that is reconstituted with Sterile Water for Injection (SWFI), USP, and administered as a subcutaneous (SC) injection. Each 202.5 mg vial of omalizumab also contains L-histidine (1.8 mg), L-histidine hydrochloride monohydrate (2.8 mg), polysorbate 20 (0.5 mg) and sucrose (145.5 mg) and is designed to deliver 150 mg of omalizumab in 1.2 mL after reconstitution with 1.4 mL SWFI, USP.

Side Effects

Generalised pain, arthralgia, myalgia, fatigue, dizziness, earache, headache, GI disturbances, fractures, pruritus, alopecia, dermatitis, upper resp tract infections, viral infections, sinusitis, pharyngitis, flu-like illness, systemic eosinophilia (e.g. Churg-Strauss syndrome).

Toxicity

Anaphylaxis

Anaphylaxis may occur rarely with this agent, either after the first dose or multiple doses , . Anaphylaxis presenting clinically as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported during and after this use of this drug. Therefore, close clinical monitoring should be performed during and shortly after administration .

Maximum Dosage

The maximum tolerated dosage of omalizumab has not yet been determined. Single intravenous (IV) doses of up to 4000 mg have been administered to patients without evidence of dose-limiting toxicity. The highest cumulative dose administered to patients was 44,000 mg over a 20 week time period, which was not associated with any toxicities .

The use in Pregnancy

The data with omalizumab use in pregnant women are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as omalizumab, are transported across the placenta in a linear fashion as a pregnancy progresses; therefore, potential effects on a fetus are likely to be greater in frequency during the second and third trimesters .

In women with inadequately or moderately controlled asthma, the current evidence suggests that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small fetal size .

The use During Breastfeeding

There is no information regarding the presence of omalizumab in human milk, the effects on the breastfed infant, or the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for omalizumab and any potential adverse effects on the breastfed child from omalizumab or from the underlying maternal condition .

Precaution

Not intended for treatment of acute asthma exacerbations, acute bronchospasm or status asthmaticus. Patient at risk of parasitic infections. May increase risk of malignancy. Delayed onset of anaphylaxis, it usually occurs 2 hr after admin but may also occur up to 4 days to >1 yr after initiation of regular treatment. Avoid abrupt withdrawal of corticosteroid therapy. Renal and hepatic impairment. Childn. Pregnancy and lactation.

Food Interaction

Xolair Prefilled Syringe Disease Interaction

Moderate: malignancies

Volume of Distribution

The apparent volume of distribution of omalizumab in patients with asthma after subcutaneous administration was 78 ± 32 mL/kg. In patients with CIU, the distribution of omalizumab was similar to that in asthmatic patients .

Elimination Route

After subcutaneous administration in pharmacokinetic studies, omalizumab was absorbed with a mean absolute bioavailability of 62% . After the administration of a single subcutanous dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly. The peak serum concentrations peaked after an average of 7­-8 days. In patients with CIU, the peak serum concentration was reached at a similar time after a single SC dose. The pharmacokinetics of omalizumab was linear at doses which were higher than 0.5 mg/kg. In patients with asthma, after several 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 one dose. In patients with CIU, omalizumab showed linear pharmacokinetics in the dose range of 75 mg to 600 mg administered as a single subcutaneous dose. After repeated dosing from 75mg-300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose .

Half Life

In chronic idiopathic urticaria (CIU) patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days .

In asthmatic patients omalizumab serum elimination half-life averaged 26 days .

Clearance

In pharmacokinetic studies, the clearance of omalizumab involved IgG clearance as well as clearance by specific binding and complex formation with its target ligand, IgE , .

The apparent clearance averaging 2.4 ± 1.1 mL/kg/day was measured in asthmatic patients .

In chronic idiopathic urticaria (CIU) patients, at steady state, based on population pharmacokinetics, omalizumab apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient).

Elimination Route

Liver elimination of IgG includes degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also shown to be excreted in bile, in pharmacokinetic studies .

Pregnancy & Breastfeeding use

Pregnancy Category B. Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

Contraindication

Severe hypersensitivity reaction to Xolair Prefilled Syringe or any ingredient of Xolair Prefilled Syringe

Acute Overdose

The maximum tolerated dose of Xolair Prefilled Syringe has not been determined. Single intravenous doses of 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, which was not associated with toxicities.

Storage Condition

Store between 2-8°C. May be transferred at room temp. Do not freeze. Following reconstitution, protect from direct sunlight. Stable for up to 8 hr if refrigerated or 4 hr if at room temp.

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