Xolair

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to omalizumab injection.

Before having any laboratory test, tell your doctor and the laboratory personnel that you are receiving omalizumab injection or if you have received omalizumab injection within the past year.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

The maximum tolerated dose of Xolair 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.

Some people using omalizumab have had a severe, life-threatening allergic reaction to this medication, either right after the injection or hours later. Allergic reaction may occur even after using the medication regularly for a year or longer.

Get emergency medical help if you have any of these signs of an allergic reaction: wheezing, tightness in your chest, trouble breathing; hives or skin rash; feeling anxious or light-headed, fainting; warmth or tingling under your skin; or swelling of your face, lips, tongue, or throat.

Asthma is often treated with a combination of different drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

If you also use a steroid medication, do not stop using the steroid suddenly or you may have unpleasant withdrawal symptoms. Talk with your doctor if any of your asthma medications do not seem to work as well in treating or preventing attacks.

Your symptoms may not improve right away once you start receiving omalizumab. For best results, keep receiving the medication as directed. Talk with your doctor if your symptoms do not improve after a few weeks of treatment.

Use omalizumab regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Using this medication may increase your risk of certain types of cancers of the breast, skin, prostate, or salivary gland. Talk to your doctor about your individual risk.

Before receiving Xolair, tell your doctor:

• if you are allergic to Xolair or any other medicine
• if you will be traveling to (or live in) areas that have high risk for parasitic infections
• if you are pregnant
• if you are breastfeeding

Tell your doctor about all the medicines you take including prescription medicines, vitamins, and herbal supplements.

WARNING: Anaphylaxis

Anaphylaxis presenting as bronchospasm, hypotension, syncope, urticaria, and/or angioedema of the throat or tongue, has been reported to occur after administration of Xolair. Anaphylaxis has occurred as early as after the first dose of Xolair, but also has occurred beyond 1 year after beginning regularly administered treatment. Because of the risk of anaphylaxis, observe patients closely for an appropriate period of time after Xolair administration. Health care providers administering Xolair should be prepared to manage anaphylaxis that can be life-threatening. Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur.

Contraindications

• Known history of severe hypersensitivity to omalizumab or any ingredient in the formulation.1 8 9

Warnings/Precautions

Warnings

Anaphylaxis (e.g., bronchospasm, hypotension, syncope, urticaria, angioedema of throat or tongue) reported in patients after administration.1 8 Other signs and symptoms of anaphylaxis included wheezing or dyspnea, dizziness, throat tightness, cough, cutaneous angioedema, generalized pruritus, rapid or weak heartbeat, anxiety (e.g., feeling of impending doom), hoarseness, dysphagia, flushing or warm feeling.1 8 9 Most cases of anaphylaxis occurred within first 60 minutes after first or second dose, but may occur after >1 year of maintenance therapy.1 8 10

Other Warnings/Precautions

Slightly higher rate of adverse cardiovascular and cerebrovascular effects (transient ischemic attacks [TIAs], MI, sudden and unexpected chest pain, pulmonary hypertension, pulmonary or venous thromboembolism, unstable angina) observed in patients receiving omalizumab in a 5-year study.1 13 Degree of increased risk of cardiovascular and cerebrovascular events difficult to quantify based on these results.1 13

Advise patients with asthma to not discontinue omalizumab before consulting their clinician.12 13

Be aware of the potential increased risk of cardiovascular and cerebrovascular events.12 Report all such adverse events to FDA MedWatch Program by phone (800-FDA-1088), fax (800-FDA-0178), through the Internet (), or by mail (MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787).8 12 13

Breast, melanoma, non-melanoma skin, prostate, parotid gland neoplasms, and other types of neoplasms observed with <1 year of therapy.1 Risk of malignancy with longer exposure to omalizumab or use in patients at higher risk for malignancy (e.g., geriatric individuals, current smokers) not known.1 4

FDA's review of data from a 5-year study of omalizumab revealed no difference in cancer rates of patients receiving omalizumab compared with placebo, but a potential increased risk of malignancy cannot be ruled out.1 13 Report all such adverse events to FDA MedWatch Program.13

Should be administered by a clinician familiar with management of potentially life-threatening anaphylaxis in a setting where parenteral drugs, oxygen, and equipment are immediately available.1 8 10 Anaphylaxis can occur after any dose of omalizumab, even if prior doses were well tolerated;1 8 9 onset of anaphylaxis may be delayed (e.g., up to 4 days) after administration.1 8 9 Monitor patients following administration (e.g., 2 hours following administration of at least the first 3 doses); optimal observation period not established.1 4 8 10 If a severe hypersensitivity reaction occurs, discontinue drug.1 4 8 9 (See Sensitivity Reactions under Cautions.)

Not effective in alleviating acute asthma exacerbations; do not use for treatment of acute bronchospasm or status asthmaticus.1

Systemic eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, reported rarely; in almost all cases, these events were associated with reduction of oral corticosteroid therapy.1 Be alert to the development of such manifestations; causal relationship not established.1

Postmarketing reports of a constellation of signs and symptoms (e.g., arthritis/arthralgia, rash, fever, lymphadenopathy) similar to serum sickness.1

Onset of symptoms reported to occur 1–5 days after first or subsequent injections of omalizumab, with recurrence following additional doses in some patients.1

If patient develops such signs and symptoms, discontinue omalizumab.1

Increased incidence and risk of helminthic infection.1 Monitor patients who are at high risk for geohelminthic infections during therapy.1 6 Insufficient data available to determine the duration of monitoring for such infections after treatment discontinuance.1

Serum total IgE concentrations increase following administration resulting from formation of omalizumab-IgE complexes.1 Such elevations may persist for up to 1 year following drug discontinuance.1

Do not use serum total IgE concentrations obtained <1 year following discontinuance of drug to reassess dosing regimen for patients with asthma; these concentrations may not reflect steady-state free IgE concentrations.1 (See Dosage under Dosage and Administration.)

In clinical studies in patients with asthma, antibodies to omalizumab detected in <0.1% of patients receiving the drug.1

Although data were incomplete, no antibodies to omalizumab reported in patients receiving the drug in clinical trials for treatment of chronic idiopathic urticaria.1

Specific Populations

Category B. Pregnancy registry at 866-496-5247 or .1

Distributed into milk in cynomolgus monkeys.1 Since IgG distributes into milk in humans, it is expected that omalizumab (IgG1κ monoclonal antibody) will be present in human milk.1 Use with caution.1

Use in children <12 years of age not recommended.1

Assessment of risks and benefits does not support use in pediatric patients with allergic asthma 6 to <12 years of age.1

Safety and efficacy not evaluated to date in patients <6 years of age with allergic asthma or in those <12 years of age with chronic idiopathic urticaria.1

Insufficient experience in patients ≥65 years of age to determine whether they respond differently from younger adults.1

Common Adverse Effects

Patients with asthma: Arthralgia, general pain, leg pain, fatigue, dizziness, fracture, arm pain, pruritus, dermatitis, earache.1

Patients with chronic idiopathic urticaria: Headache,1 14 16 nasopharyngitis,1 sinusitis,1 16 arthralgia,1 14 nausea,1 cough,1 upper respiratory tract infection (sometimes viral).1 16

Storage

Parenteral

Ship at ≤30°C.1 Store at 2–8°C.1 10 When reconstituted with sterile water for injection, solutions prepared in single-use vials are stable for ≤8 hours at 2–8°C or ≤4 hours at room temperature.1 Protect reconstituted vials from sunlight.1

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of omalizumab injection to treat asthma in children younger than 6 years of age and CIU in children younger than 12 years of age is not recommended. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of omalizumab injection in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Asthma attack or
• Bronchospasm (breathing problem), acute or
• Other allergic conditions (besides asthma)—Should not be used for patients with these conditions.

• Cancer, or history of or
• Parasite infection—Use with caution. May make these conditions worse.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

• Cough
• difficulty with swallowing
• dizziness
• fast heartbeat
• hives, itching, or skin rash
• malignant tumor
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• tightness in the chest
• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding
• blistering
• body aches or pain
• burning
• chills
• cold or flu-like symptoms
• coldness
• congestion
• discoloration of the skin
• dryness or soreness of the throat
• feeling of pressure
• fever
• headache
• hoarseness
• itching
• leg pain
• lumps
• muscle or joint pain
• numbness
• pain
• pain or tenderness around the eyes and cheekbones
• redness
• runny nose
• scarring
• sore throat
• soreness
• stinging
• stuffy or runny nose
• swelling
• tender, swollen glands in the neck
• tenderness
• tingling
• ulceration
• voice changes
• warmth

• Arm pain
• blistering, crusting, irritation, itching, or reddening of the skin
• body produces substance that can bind to drug making it less effective or cause side effects
• cracked, dry, or scaly skin
• earache
• itching skin

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to treat asthma.
• It is used to treat hives.

For asthma:

• Do not use this medicine to treat an asthma attack. Use a rescue inhaler. Talk with your doctor.

• If you need to store Xolair at home, talk with your doctor, nurse, or pharmacist about how to store it.

Mechanism of Action

Asthma

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

Chronic Idiopathic Urticaria

Omalizumab binds to IgE and lowers free IgE levels. Subsequently, IgE receptors (FcεRI) on cells down-regulate. The mechanism by which these effects of omalizumab result in an improvement of CIU symptoms is unknown.

Pharmacodynamics

Asthma

In clinical studies, serum free IgE levels were reduced in a dose dependent manner within 1 hour following the first dose and maintained between doses. Mean serum free IgE decrease was greater than 96% using recommended doses. Serum total IgE levels (i.e., bound and unbound) increased after the first dose due to the formation of omalizumab:IgE complexes, which have a slower elimination rate compared with free IgE. At 16 weeks after the first dose, average serum total IgE levels were five-fold higher compared with pre-treatment when using standard assays. After discontinuation of Xolair dosing, the Xolair-induced increase in total IgE and decrease in free IgE were reversible, with no observed rebound in IgE levels after drug washout. Total IgE levels did not return to pre-treatment levels for up to one year after discontinuation of Xolair.

Chronic Idiopathic Urticaria

In clinical studies in CIU patients, Xolair treatment led to a dose-dependent reduction of serum free IgE and an increase of serum total IgE levels, similar to the observations in asthma patients. Maximum suppression of free IgE was observed 3 days following the first subcutaneous dose. After repeat dosing once every 4 weeks, predose serum free IgE levels remained stable between 12 and 24 weeks of treatment. Total IgE levels in serum increased after the first dose due to the formation of omalizumab-IgE complexes which have a slower elimination rate compared with free IgE. After repeat dosing once every 4 weeks at 75 mg up to 300 mg, average predose serum total IgE levels at Week 12 were two-to three-fold higher compared with pre-treatment levels, and remained stable between 12 and 24 weeks of treatment. After discontinuation of Xolair dosing, free IgE levels increased and total IgE levels decreased towards pre-treatment levels over a 16-week follow-up period.

Pharmacokinetics

After SC administration, omalizumab was absorbed with an average absolute bioavailability of 62%. Following a single SC dose in adult and adolescent patients with asthma, omalizumab was absorbed slowly, reaching peak serum concentrations 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 greater than 0.5 mg/kg. In patients with asthma, following multiple doses of Xolair, 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. In patients with CIU, omalizumab exhibited linear pharmacokinetics across the dose range of 75 mg to 600 mg given as single subcutaneous dose. Following repeat dosing from 75 to 300 mg every 4 weeks, trough serum concentrations of omalizumab increased proportionally with the dose levels.

In vitro, omalizumab formed complexes of limited size with IgE. Precipitating complexes and complexes larger than 1 million daltons in molecular weight were not observed in vitro or in vivo. Tissue distribution studies in Cynomolgus monkeys showed no specific uptake of 125I-omalizumab by any organ or tissue. The apparent volume of distribution of omalizumab in patients with asthma following SC administration was 78 ± 32 mL/kg. In patients with CIU, based on population pharmacokinetics, distribution of omalizumab was similar to that in patients with asthma.

Clearance of omalizumab involved IgG clearance processes as well as clearance via specific binding and complex formation with its target ligand, IgE. Liver elimination of IgG included degradation in the liver reticuloendothelial system (RES) and endothelial cells. Intact IgG was also excreted in bile. In studies with mice and monkeys, omalizumab:IgE complexes were eliminated by interactions with Fcγ receptors within the RES at rates that were generally faster than IgG clearance. In asthma patients omalizumab serum elimination half-life averaged 26 days, with apparent clearance averaging 2.4 ± 1.1 mL/kg/day. Doubling body weight approximately doubled apparent clearance. In CIU patients, at steady state, based on population pharmacokinetics, omalizumab serum elimination half-life averaged 24 days and apparent clearance averaged 240 mL/day (corresponding to 3.0 mL/kg/day for an 80 kg patient).

Special Populations

Asthma

The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics in patients with asthma. Analyses of these data suggested that no dose adjustments are necessary for age (6-76 years), race, ethnicity, or gender.

Chronic Idiopathic Urticaria

The population pharmacokinetics of omalizumab was analyzed to evaluate the effects of demographic characteristics and other factors on omalizumab exposure in patients with CIU. Covariate effects were evaluated by analyzing the relationship between omalizumab concentrations and clinical responses. These analyses demonstrate that no dose adjustments are necessary for age (12 to 75 years), race/ethnicity, gender, body weight, body mass index or baseline IgE level.

Call your doctor for instructions if you miss an appointment for your injection.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Some people using Xolair have had a severe, life-threatening allergic reaction either right after the injection or hours later. Allergic reaction may occur even after using the medication regularly for a year or longer.

Get emergency medical help if you have any signs of an allergic reaction to Xolair:

• hives, rash;

• anxiety or fear, feeling like you might pass out;

• flushing (warmth, redness, or tingly feeling);

• chest tightness, wheezing, feeling short of breath, difficult breathing;

• fast or weak heartbeats; or

• swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• bronchospasm (wheezing, chest tightness, trouble breathing);

• fever, swollen glands, rash or itching, joint pain, or general ill feeling;

• chest pain spreading to your jaw or shoulder, coughing up blood;

• sudden numbness or weakness (especially on one side of the body), problems with vision or speech;

• pain, swelling, warmth, or redness in one or both legs;

• new or worsening cough, fever, trouble breathing; or

• skin rash, bruising, severe tingling, numbness, pain, muscle weakness.

Common Xolair side effects may include:

• itching, mild rash;

• joint pain, bone fractures;

• arm or leg pain;

• nausea;

• dizziness, tired feeling;

• ear pain; or

• cold symptoms such as stuffy nose, sneezing, sinus pain, cough, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.