Active ingredients: Omalizumab
Xolair 75 mg powder and solvent for solution for injection
Xolair package inserts are available for pack sizes:- Xolair 75 mg powder and solvent for solution for injection
- Xolair 150 mg powder and solvent for solution for injection
Why is Xolair used? What is it for?
The active ingredient of Xolair is omalizumab. Omalizumab is a synthetic protein similar to natural proteins produced by the body; it belongs to a class of medicines called monoclonal antibodies.
It is used to prevent the worsening of asthma by controlling the symptoms of severe allergic asthma in adults and adolescents (12 years and older) and children (6 to less than 12 years old) who are already receiving asthma medicines. but in which asthma symptoms are not well controlled by drugs such as high-dose inhaled steroids or inhaled beta-agonists.
Xolair blocks a substance called immunoglobulin E (IgE), which is produced by the body. IgE plays a key role in causing allergic asthma.
Contraindications When Xolair should not be used
You should not be given Xolair
- if you are allergic to omalizumab or any of the other ingredients of this medicine (listed in section 6).
If you think you are allergic to any of the ingredients please tell your doctor as Xolair should not be given to you.
Precautions for use What you need to know before taking Xolair
Xolair contains a protein, and in some people the protein can cause severe allergic reactions.
The signs include a rash, difficulty breathing, swelling or feeling faint. If you have an allergic reaction after taking Xolair, contact a doctor as soon as possible.
A special type of allergic reaction, called serum sickness, has been observed in patients treated with Xolair. Symptoms of serum sickness can be one or more of the following: joint pain with or without swelling or stiffness, rash, fever, swollen lymph nodes, muscle pain. If you experience any of these symptoms, or in particular if you experience a combination of these symptoms, contact your doctor immediately.
Churg-Strauss syndrome and eosinophilic syndrome have been observed in patients treated with Xolair. Symptoms may be one or more of the following: swelling, pain or rash around blood or lymph vessels, elevated level of a specific type of white blood cell (marked eosinophilia), worsening of breathing problems, nasal congestion, heart problems, pain , numbness, tingling in the arms and legs. If you experience any of these symptoms, or in particular if you experience a combination of these symptoms, contact your doctor immediately.
Talk to your doctor before you are given Xolair:
- if you have kidney or liver problems
- if you have a disorder in which your immune system attacks part of your body (autoimmune disease)
- if you live in regions where infections caused by parasites are common or if you plan to travel to one of these regions because Xolair may decrease your resistance to these infections.
Xolair does not cure acute asthma symptoms, such as a sudden asthma attack. Therefore Xolair should not be used to treat these symptoms.
Do not use Xolair to prevent or treat other allergic-type disorders such as sudden allergic reactions, hyperimmunoglobulin E syndrome (an inherited immune disorder), aspergillosis (a fungal lung disease), food allergy, eczema or hay fever because Xolair has not been studied in these conditions.
Children (under 6 years of age)
Xolair should not be given to children under 6 years of age. There are insufficient data in this age group.
Interactions What medications or foods may change the effect of Xolair
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines.
This is especially important if you are taking:
- medicines to treat an infection caused by a parasite, as Xolair may reduce the effect of these medicines,
- inhaled corticosteroids and other medicines for allergic asthma.
Warnings It is important to know that:
Pregnancy and breastfeeding
You should not be given Xolair during pregnancy unless your doctor considers it necessary.
If you are planning to become pregnant, tell your doctor before starting treatment with Xolair. Your doctor will discuss with you the benefits and potential risks of taking this medicine during pregnancy.
If you become pregnant while taking Xolair, tell your doctor immediately.
If you are breastfeeding you should not be given Xolair.
Driving and using machines
Xolair is unlikely to affect the ability to drive and use machines.
Dosage and method of use How to use Xolair: Dosage
Instructions on how to use Xolair are provided in the section "Information for healthcare professionals".
Your doctor will determine how much Xolair you need and how often it will be given to you. This depends on your body weight and the results of the blood test carried out before starting treatment to measure the level of IgE in your blood.
Xolair is given to you by a doctor or nurse as an injection under the skin.
Follow the instructions of your doctor or nurse carefully.
Amount administered
You will be given 1 to 4 injections at a time, every two weeks, or every four weeks.
Continue to take your current asthma medicine during treatment with Xolair. Do not stop taking asthma medicines without first checking with your doctor.
You may not notice immediate improvement in your asthma after starting Xolair therapy. The full effect is usually reached after 12-16 weeks.
Use in children and adolescents
Xolair can be used in children and adolescents aged 6 years and older who are already taking medicines for asthma but whose asthma symptoms are not well controlled by medicines such as high dose inhaled steroids or inhaled beta agonists. Your doctor will know how much Xolair your child needs and how often they will need to take it. This will depend on the child's weight and the results of the blood test taken before starting treatment to measure the amount of IgE in the child. blood of the child.
If you have not taken a dose of Xolair
Contact your doctor or hospital as soon as possible to make a new appointment.
If you stop taking Xolair
Do not stop taking Xolair unless your doctor tells you to. Interrupting or stopping treatment with Xolair can cause asthma symptoms to return.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Xolair
Like all medicines, this medicine can cause side effects, although not everybody gets them. The side effects caused by Xolair are usually mild to moderate but can occasionally be serious.
Serious side effects include:
Rare side effects (may affect up to 1 in 1,000 people)
- Sudden severe allergic reactions: if you notice sudden severe signs of allergy or the combined appearance of signs such as rash, itching or hives on the skin, swelling of the face, lips, tongue, larynx (vocal cords), windpipe or other parts of the body, rapid heartbeat, dizziness and lightheadedness, shortness of breath, wheezing or difficulty in breathing, or any other new symptoms, tell your doctor or nurse immediately. If you have a history of severe, unrelated allergic reactions (anaphylaxis) to Xolair, you may have an increased risk of developing a severe allergic reaction following the use of Xolair.
- Systemic lupus erythematosus (SLE). Symptoms may include muscle pain, joint pain and swelling, and a rash. It can also manifest other symptoms, such as fever, weight loss, and fatigue.
Not known (frequency cannot be estimated from the available data)
- One or more of the following symptoms: swelling, pain or rash around blood or lymphatic vessels, elevated level of a specific type of white blood cell (marked eosinophilia), worsening of breathing problems, nasal congestion, heart problems, pain, numbness, tingling in the arms, legs (signs of the so-called "Churg-Strauss syndrome or hypereosinophilic syndrome").
- Low blood platelet count with symptoms such as bleeding or bruising easier than usual.
- Appearance of any of the following symptoms, especially if associated: joint pain with or without swelling or stiffness, rash, fever, swollen lymph nodes, muscle pain (signs of serum sickness).
If you get any of these symptoms tell your doctor or nurse immediately.
Other side effects include:
Very common side effects (may affect more than 1 in 10 people)
- fever (in children)
Common side effects (may affect up to 1 in 10 people)
- reactions at the injection site such as pain, swelling, itching and redness
- pain in the upper belly (in children)
- headache (very common in children)
Uncommon side effects (may affect up to 1 in 100 people)
- feeling dizzy, sleepy or tired
- tingling or numbness in the hands or feet
- fainting, low blood pressure when sitting or standing (postural hypotension), flushing
- sore throat, cough, acute breathing problems
- feeling sick (nausea), diarrhea, indigestion
- itching, hives, rash, increased sensitivity of the skin to the sun
- weight gain
- flu-like symptoms
- swollen arms
Rare side effects (may affect up to 1 in 1,000 people)
- parasite infection
Not known (frequency cannot be estimated from the available data)
- joint pain, muscle and joint swelling
- hair loss
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last day of that month.
- Store in a refrigerator (2 ° C - 8 ° C). Do not freeze.
Deadline "> Other information
What Xolair contains
- The active ingredient is omalizumab. One vial contains 75 mg of omalizumab. After reconstitution one vial contains 125 mg / ml of omalizumab (75 mg in 0.6 ml).
- The other ingredients are sucrose, L-histidine, L-histidine hydrochloride monohydrate, polysorbate 20.
What Xolair looks like and contents of the pack
Xolair 75 mg powder and solvent for solution for injection is supplied as a white to off-white powder in a small glass vial together with a vial containing 2 ml of water for injections. Before being injected by the doctor or nurse, the powder is reconstituted in water.
Xolair is available in packs containing one vial of powder for solution for injection and one ampoule with 2 ml of water for injections.
Xolair is also available in vials containing 150 mg of omalizumab.
Deadline "> Information for healthcare professionals
The following information is intended for healthcare professionals only:
The lyophilized medicine takes 15-20 minutes to dissolve, although in some cases it may take longer. The fully reconstituted medicinal product appears clear to slightly opalescent, colorless to pale brownish-yellow and may have small bubbles or foam around the edge of the vial. Due to the viscosity of the reconstituted medicinal product, care must be taken to withdraw all the medicinal product from the vial before expelling any excess air or solution from the syringe in order to obtain 0.6 ml.
To prepare vials of Xolair 75 mg for subcutaneous administration, follow these instructions:
- Draw 0.9 ml of water for injections from the vial into a syringe equipped with a large 18 gauge needle.
- With the vial held upright on a flat surface, insert the needle and transfer the water for injections into the vial containing the lyophilized powder following standard sterile techniques, directing the water for injections directly onto the powder.
- Holding the vial upright, vigorously invert (do not shake) repeatedly for approximately 1 minute to evenly moisten the powder.
- To help dissolve, after completing step 3, gently invert the vial for 5-10 seconds, approximately every 5 minutes, to dissolve any remaining solid particles. It should be noted that in some cases it may take more than 20 minutes for the powder to dissolve completely. In this case, repeat step 4 until no more gel-like particles are visible in the solution. When the medicine is completely 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 slightly opalescent, colorless to pale brownish yellow Do not use if solid particles are present.
- Invert the vial for at least 15 seconds to allow the solution to flow to the stopper. Using a new 3 ml syringe, equipped with a large 18 gauge needle, insert the needle into the upside down vial. Keeping the vial upside down, place the tip of the needle at the 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 towards the end of the syringe barrel to draw all of the solution out of the inverted vial.
- Replace the 18 gauge needle with a 25 gauge needle for subcutaneous injection.
- Expel air, larger bubbles, and any excess solution in order to obtain the required 0.6 ml solution. A thin layer of small bubbles may remain on top of the solution in the syringe. As the solution is slightly viscous, administration of the solution by injection under the skin may take 5-10 seconds. The vial delivers 0.6 ml (75 mg) of Xolair.
- The injections are administered subcutaneously in the deltoid region of the arm or in the thigh.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
XOLAIR 75 MG POWDER AND SOLVENT FOR INJECTABLE SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
One vial contains 75 mg of omalizumab *.
After reconstitution one vial contains 125 mg / ml of omalizumab (75 mg in 0.6 ml).
* Omalizumab is a humanised monoclonal antibody produced by recombinant DNA technology in a Chinese Hamster Ovary (CHO) cell line.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Powder and solvent for solution for injection.
Off-white lyophilized powder.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Xolair is indicated in adults, adolescents and children aged 6 to
Treatment with Xolair should only be considered for patients with known IgE (immunoglobulin E) mediated asthma (see section 4.2).
Adults and adolescents (12 years of age and older)
Xolair is indicated, as an adjunct therapy, to improve asthma control in patients with severe persistent allergic asthma than skin or reactivity test in vitro tested positive for a perennial aeroallergen and have reduced lung function (FEV1 day symptoms or nocturnal awakenings and in patients with documented severe repeated asthma exacerbations, despite the daily intake of high doses of inhaled corticosteroids, plus a long-term beta2-agonist duration of action by inhalation.
Children (from 6 to
Xolair is indicated, as an adjunct therapy, to improve asthma control in patients with severe persistent allergic asthma than skin or reactivity test. in vitro tested positive for a perennial aeroallergen and have frequent daytime symptoms or nocturnal awakenings and in patients with documented repeated severe asthma exacerbations, despite the daily intake of high doses of inhaled corticosteroids, plus a long-acting beta2-agonist by inhalation.
04.2 Posology and method of administration -
Treatment with Xolair should be initiated by physicians experienced in the diagnosis and treatment of severe persistent asthma.
Dosage
The appropriate dose and frequency of administration of Xolair are determined by baseline IgE levels (IU / ml), measured before starting treatment, and body weight (kg). Prior to administration of the starting dose, patients should determine their IgE levels by any commercially available serum total IgE test for the purpose of determining their dose. Based on these determinations, 75 to 600 mg of Xolair in 1-4 injections may be required for each administration.
Benefits are less likely to be observed in patients with IgE levels below 76 IU / ml (see section 5.1). Before starting therapy, the physician must ensure that adult and adolescent patients with IgE levels below 76 IU / ml and children (6 to in vitro (RAST) to a perennial allergen.
See Table 1 for conversion and Tables 2 and 3 for dose determination in adults, adolescents and children 6 to
For patients whose baseline IgE levels or body weight in kilograms are outside the dose table limits, Xolair should not be given.
The maximum recommended dose is 600 mg of omalizumab every two weeks.
Table 1: Conversion from dose to number of vials, number of injections and total volume injected with each administration
a0.6 ml = maximum extractable volume per vial (Xolair 75 mg).
b1.2 ml = maximum extractable volume per vial (Xolair 150 mg).
or use 0.6 ml from a 150 mg vial.
Table 2: ADMINISTRATION EVERY 4 WEEKS. Doses of Xolair (milligrams per dose) given by subcutaneous injection every 4 weeks
Table 3: ADMINISTRATION EVERY 2 WEEKS. Doses of Xolair (milligrams per dose) given by subcutaneous injection every 2 weeks
Duration of treatment, monitoring and dose adjustment
Xolair is intended for long-term treatment. Clinical studies have shown that it takes at least 12-16 weeks for Xolair treatment to be effective. After 16 weeks of starting Xolair therapy, patients should be evaluated by their doctor to see if the treatment is effective before further injections are given. The decision to continue Xolair therapy at the end of week 16, or on subsequent occasions, should be based on the observation of a marked improvement in overall asthma control (see section 5.1. Physician's overall assessment of treatment efficacy). .
Discontinuation of Xolair treatment usually 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 discontinuation of treatment. Therefore, re-measurement of IgE levels during treatment with Xolair cannot be used as a guide for dose determination. Dose determination after an "interruption of treatment of less than one year duration should be based on the serum IgE levels obtained at the time of the initial dose determination. Total serum IgE levels can be re-measured for dose determination if treatment with Xolair was discontinued for a year or more.
Doses should be adjusted for significant changes in body weight (see Tables 2 and 3).
Special populations
Elderly (65 years of age and older)
There are limited data on the use of Xolair in patients over 65 years of age but there is no evidence that elderly patients require a different dosage from that of younger adult patients.
Impaired renal or hepatic function
No studies on the effect of impaired renal or hepatic function on the pharmacokinetics of Xolair have been performed. clearance of omalizumab is dominated by the reticulo-endothelial system (RES), it is unlikely to be affected by renal or hepatic impairment. While no particular dose adjustment is recommended, Xolair should be administered with caution in these patients (see section 4.4).
Pediatric population
The safety and efficacy of Xolair in children aged less than 6 years have not been established. There are no data available.
Method of administration
For subcutaneous administration only. Do not administer intravenously or intramuscularly.
The injections are given subcutaneously in the deltoid region of the arm. Alternatively, injections can be given in the thigh if there are reasons that preclude administration in the deltoid region.
There is limited experience with self-administration of Xolair. Therefore treatment should only be performed by a healthcare professional.
For instructions on reconstitution of the medicinal product before administration, see section 6.6 and the section with information for healthcare professionals in the package leaflet.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use -
General
Xolair is not indicated for the treatment of acute asthma exacerbations, acute bronchospasm or asthma.
Xolair has not been studied in patients with hyperimmunoglobulin E syndrome or allergic bronchopulmonary aspergillosis or for the prevention of anaphylactic reactions, including those caused 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 insufficiency (see section 4.2). Caution should be exercised in administering Xolair to these patient populations.
It is not recommended to abruptly discontinue treatment with systemic or inhaled corticosteroids after initiation of Xolair therapy. Decreases in corticosteroid doses should be done under direct medical supervision and may need to be done gradually.
Disorders of the immune system
Type I allergic reactions
Local or systemic type I allergic reactions, including anaphylaxis and anaphylactic shock, may occur with omalizumab, even with onset after a long period of treatment. Most of these reactions occur within 2 hours of the first and subsequent injection. of Xolair but some occurred beyond 2 hours and even beyond 24 hours after injection. Therefore, medicinal products for the treatment of anaphylactic reactions should always be available for immediate use following administration of Xolair. Patients should be advised that such reactions are possible and that if they occur, medical attention should be sought immediately. .
Anaphylactic reactions were rare in clinical studies (see section 4.8).
In clinical studies, antibodies to omalizumab were detected in a small number of patients (see section 4.8). The clinical relevance of anti-Xolair antibodies is not well known.
Serum sickness
Serum sickness and serum sickness-like reactions, which are delayed type III allergic reactions, have been observed in patients treated with humanized monoclonal antibodies, including omalizumab. The suggested pathophysiological mechanism includes formation and deposition immune complexes following the formation of antibodies to omalizumab. This usually occurs 1-5 days after the first or subsequent injection, even after a long duration of treatment. Symptoms suggestive of serum sickness include arthritis / arthralgia, rash (urticaria or other forms), fever and lymphadenopathy Antihistamines and cortisones may be helpful in preventing or treating these disorders and patients should be advised to report any suspicious symptoms.
Churg-Strauss syndrome and hypereosinophilic syndrome
Patients with severe asthma may rarely have systemic hypereosinophilic syndrome or allergic granulomatous eosinophilic vasculitis (Churg-Strauss syndrome), both of which are usually treated with systemic corticosteroids.
In rare cases, patients on 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.
Physicians should be advised that marked eosinophilia, vasculitic rash, worsening pulmonary symptoms, sinus abnormalities, cardiac complications, and / or neuropathy may develop in such patients.
Omalizumab discontinuation should be considered in all severe cases with the aforementioned immune system disorders.
Parasitic infections (helminths)
IgE may be involved in the immunological response to some helminth infections. In patients with a chronic high risk of helminth infection, a placebo-controlled study demonstrated a slight increase in the infection rate with omalizumab, although the course, severity, and response to treatment of the infection were unaffected. The infection rate was unaffected. in the overall clinical program, 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 infections, particularly when traveling. in areas where helminth infections are endemic. Should patients fail to respond to recommended anti-helminth treatment, consideration should be given to discontinuing Xolair therapy.
04.5 Interactions 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 decrease 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 omalizumab clearance; therefore, the drug-drug interaction potential is limited. No drug or vaccine interaction studies have been performed. Xolair: There are no pharmacological reasons to expect that commonly prescribed asthma medications will interact with omalizumab.
In clinical studies, Xolair was commonly used in combination with inhaled and oral corticosteroids, inhaled short and long-acting beta agonists, leukotriene antagonists, theophylline and oral antihistamines. There has been no indication of this. alteration of the safety of Xolair with these other commonly used asthma medicines. There are limited data on the use of Xolair in combination with specific immunotherapy (hyposensitizing therapy). In a clinical trial where Xolair was administered concomitantly with immunotherapy, the safety and efficacy of Xolair in combination with specific immunotherapy did not were different from those of Xolair alone.
04.6 Pregnancy and breastfeeding -
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 (see section 5.3). Omalizumab crosses the placental barrier and potential harm to the fetus does not omalizumab has been associated with age-dependent platelet reduction in non-human primates, with relatively higher sensitivity in juvenile animals (see section 5.3). Xolair should not be used during pregnancy unless clearly necessary.
Feeding time
It is unknown whether omalizumab is excreted in human breast milk. Available data in non-human primates have shown excretion of omalizumab in milk (see section 5.3). A risk to the newborns / infants cannot be excluded. Omalizumab should not be administered during lactation.
Fertility
There are no data available on human fertility for omalizumab. In non-clinical studies in non-human primates specifically designed to evaluate the effect on fertility, including mating studies, no effects on male or female fertility were observed. following repeated administration of omalizumab up to doses of 75 mg / kg In addition, in separate non-clinical genotoxicity studies, no genotoxic effects were observed (see section 5.3).
04.7 Effects on ability to drive and use machines -
Xolair has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects -
Summary of the safety profile
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 pain, swelling, erythema and pruritus, and headache. In clinical trials in children aged 6 to headache, pyrexia and upper abdominal pain. Most of the reactions were mild or moderate in severity.
Table of adverse reactions
Table 4 lists adverse reactions recorded in clinical studies in the total safety population treated with Xolair, by MedDRA organ system classification and frequency. Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequencies are defined as: very common (≥1 / 10), common (≥1 / 100; post-marketing are listed with non known (frequency cannot be estimated from the available data).
Table 4: Adverse reactions
*: very common in children 6 to
**: in children from 6 to
Description of selected adverse reactions
Disorders of the immune system
For further information, see section 4.4.
Arterial thromboembolic events (ATE)
In controlled clinical trials and during interim analyzes of an observational study, a numerical imbalance of arterial thromboembolic events was observed. The definition of the composite ATE endpoint included stroke, transient ischemic attack, myocardial infarction, unstable angina, and cardiovascular death (including death from unknown cause). In the final analysis of the observational study, the ATE rate per 1,000 patient years was 7 , 52 (115 / 15,286 patient years) for patients treated with Xolair and 5.12 (51 / 9,963 patient years) for control patients. In a "multivariate control analysis of baseline cardiovascular risk factors, the hazard ratio was 1.32 (95% confidence interval 0.91-1.91). In a new pooled clinical trial analysis that included all in randomized double-blind, placebo-controlled trials lasting 8 weeks or longer, the ATE rate per 1,000 patient years was 2.69 (5 / 1,856 patient years) for patients treated with Xolair and 2.38 (4 / 1,680 patient years) for the placebo group (rate ratio 1.13, 95% confidence interval 0.24-5.71).
Platelets
In clinical studies, few patients had platelet counts below the lower limit of the normal laboratory range. None of these changes were associated with bleeding episodes or decreased hemoglobin. No patterns of persistent decreases in platelet counts, such as that observed in non-human primates (see section 5.3), have been reported in humans (patients older than at 6 years) although isolated cases of idiopathic thrombocytopenia, including severe cases, have been reported in post-marketing observations.
Parasitic infections
In patients with chronic high risk of helminth infections, a placebo-controlled study showed a slight numerical increase in the infection rate in the omalizumab group that was not statistically significant. The course, severity and response to treatment of infections remained unaffected (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. .
04.9 Overdose -
The maximum tolerated dose of Xolair has not been determined. Single intravenous doses up to 4,000 mg have been administered to patients with no evidence of dose-limiting toxicity. The highest cumulative dose administered to patients was 44,000 mg over a 20 week period and this dose did not cause any unexpected acute effects.
If overdose is suspected, the patient should be observed for any abnormal signs or symptoms. Appropriate medical treatment should be sought.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: other drugs for obstructive respiratory tract syndromes for systemic use, ATC code: R03DX05
Omalizumab is a humanized monoclonal antibody derived from recombinant DNA that selectively binds to human immunoglobulin E (IgE). The antibody is an IgG1 kappa containing human support regions along with complementary-determining regions of a mouse antibody that binds to IgE.
Mechanism of action
Omalizumab binds to IgE and prevents the binding of IgE to the high affinity receptor FCεRI, thereby reducing the amount of free IgE that can trigger the allergic cascade. In atopic individuals, omalizumab treatment also reduces the number of FCεRI receptors located on basophils.
Pharmacodynamic effects
The release in vitro histamine from basophils isolated from subjects treated with Xolair was reduced by approximately 90% following stimulation with an allergen compared to pre-treatment values.
In clinical studies, serum free IgE levels decreased in a dose-dependent manner within one hour of the first administration and remained stable between doses. One year after stopping Xolair dosing, IgE levels returned to pre-treatment levels and no rebound effect on IgE levels was observed after the drug elimination period.
Clinical efficacy and safety
Adults and adolescents aged ≥12 years
The efficacy and safety of Xolair were demonstrated in a 28-week double-blind placebo-controlled study (study 1) involving 419 severe allergic asthma patients, aged 12 to 79 years, who had reduced lung function (predicted FEV1 40-80%) and poor control of asthma symptoms despite treatment with high-dose inhaled corticosteroids and a long-acting beta2-agonist. Eligible patients had had multiple asthmatic exacerbations requiring systemic corticosteroid treatment or had been hospitalized or went to the emergency room due to a severe asthma exacerbation within the previous year despite continued high-dose corticosteroid treatment. by inhalation and with a long-acting beta2-agonist. Subcutaneous xolair or placebo was given as add-on therapy to> 1,000 micrograms beclomethasone dipropionate (or equivalent) in addition to a long-acting beta2-agonist. Maintenance therapies with oral corticosteroids, theophylline, and antagonists were allowed. leukotrienes (22%, 27%, and 35% of patients, respectively).
The frequency of asthma exacerbations requiring treatment with relatively high doses of systemic corticosteroids was the primary endpoint. Omalizumab reduced the frequency of asthma exacerbations by 19% (p = 0.153). Additional evaluations that demonstrated statistical significance (p
In a subgroup analysis, patients with pretreatment total IgE ≥76 IU / mL were more likely to achieve clinically meaningful benefit with Xolair. In these patients in study 1 Xolair reduced the frequency of asthma exacerbations by 40% (p = 0.002) In addition, additional patients from the population with total IgE ≥76 IU / mL in the Xolair program in severe asthma had clinically meaningful responses. Table 5 includes the results for the entire study 1 population.
Table 5: Study results 1
* marked improvement or complete control
** p-value for the general distribution of the valuation
Study 2 evaluated the efficacy and safety of Xolair in a population of 312 severe allergic asthma patients which matched the study population 1. Treatment with Xolair in this open-label study resulted in a 61% reduction in frequency. clinically significant asthma exacerbations compared to ongoing 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) evaluated the efficacy and safety of Xolair in patients with severe persistent asthma. some patients were not adequately controlled, however they received reduced concomitant asthma therapy compared to patients in studies 1 or 2. Studies 3-5 used exacerbation as the primary endpoint, while study 6 mainly evaluated reduction of inhaled corticosteroids .
In studies 3, 4 and 5, patients treated with Xolair had a reduction in the frequency of asthma exacerbations of 37.5% (p = 0.027), 40.3% (p
In study 6, significantly more severe allergic asthma patients treated with Xolair were able to reduce the fluticasone dose to ≤500 mcg / day with no deterioration in asthma control (60.3%) compared with the placebo group (45.8% , p
Quality of life was 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 compared to the placebo or control groups.
Overall assessment of the effectiveness of the treatment by the doctor:
The physician's overall evaluation was carried out in five studies mentioned above, as a general measure of asthma control expressed by the treating physician. The physician was able to take into account the peak expiratory flow (PEF), day and night symptoms, use of rescue medications, spirometry and exacerbations. In all five studies, a significantly higher proportion of patients treated with Xolair were believed to have achieved marked improvement or complete control of asthma compared to patients treated with placebo.
Children from 6 to
Key data supporting the safety and efficacy of Xolair in the 6 to
Study 7 is a placebo-controlled study that included a specific subgroup (N = 235) of patients as defined in this indication, treated with high doses of inhaled corticosteroids (≥500 μg / day fluticasone or equivalent) in addition to a long-acting beta-agonist.
Clinically significant exacerbation was defined as worsening of asthma symptoms in the investigator's clinical judgment and involved doubling from baseline the dose of inhaled corticosteroid for at least 3 days and / or reliever treatment with systemic corticosteroids (oral or intravenously) for at least 3 days.
In the specific subgroup of patients who received high doses of inhaled corticosteroids, the rate of asthma exacerbations was significantly lower in the omalizumab group than in the placebo group. At week 24, the difference between exacerbation rates in the two treatment groups was a 34% reduction for patients treated with omalizumab compared to placebo (ratio of percentages 0.662, p = 0.047). In the second 28-week period of double-blind treatment, the difference between rates of exacerbation in the two treatment groups was equal to a reduction of 63% for patients treated with omalizumab compared to placebo (ratio of the percentages 0.37, p
Over the course of week 52 of the double-blind treatment period (comprising 24 weeks of treatment with a fixed dose of steroids and 28 weeks of treatment with a variable dose of steroids) the difference in percentages between the treatment groups was one relative reduction of 50% (ratio of percentages 0.504, p
At the end of 52 weeks of treatment, the omalizumab group showed a greater reduction in the use of as-needed beta agonists than the placebo group, although the difference between the two treatment groups was not statistically significant. the overall assessment of treatment efficacy at the end of the 52-week double-blind treatment period, in the subgroup of severe patients with high-dose inhaled corticosteroids in combination with long-acting beta-agonists the percentage of patients with efficacy of treatment rated "excellent" was higher while the percentage of patients with treatment efficacy rated "moderate" or "poor" was lower in the group treated with omalizumab than in the group treated with placebo; the difference between the two groups was statistically significant (p
05.2 "Pharmacokinetic properties -
The pharmacokinetics of omalizumab were studied in adult and adolescent patients with allergic asthma.
Absorption
Following subcutaneous administration, omalizumab is absorbed with a mean absolute bioavailability of 62%. Following single dose subcutaneous administration in adult and adolescent asthma patients, omalizumab was absorbed slowly, reaching peak serum concentrations after a mean of 7-8 days. Omalizumab pharmacokinetics are linear at doses above 0.5 mg / kg. After multiple doses of omalizumab, the steady-state areas under the serum concentration-time curve from Day 0 to Day 14 were up to 6 times those recorded after the first dose.
Administration of Xolair in both liquid and lyophilized formulations resulted in a similar concentration-time profile of omalizumab in serum.
Distribution
In vitro, omalizumab forms small complexes with IgE. Precipitation complexes and complexes of molecular weight greater than one million daltons were not observed in vitro or in vivo. The apparent volume of distribution in patients following subcutaneous administration was 78 ± 32 ml / kg.
Elimination
Clearance of omalizumab involves IgG clearance processes as well as clearance through specific binding and complexing with its target ligand, IgE. Hepatic elimination of IgG includes degradation in the reticuloendothelial system and endothelial cells. Unchanged IgG is also excreted in the bile. In patients with asthma, the serum elimination half-life of omalizumab averages 26 days, with mean apparent clearance of 2.4 ± 1.1 ml / kg / day. Furthermore, doubling the body weight approximately doubled the apparent clearance.
Characteristics in patient populations
Age, Race / Ethnicity, Gender, Body Mass Index
The population pharmacokinetics of Xolair were analyzed to evaluate the effects of demographic characteristics. Analyzes of these limited data indicate that no dose adjustment is required based on age (6-76 years), race / ethnicity, gender or body mass index (see section 4.2).
Renal and hepatic insufficiency
There are no pharmacokinetic or pharmacodynamic data in patients with renal or hepatic impairment (see sections 4.2 and 4.4).
05.3 Preclinical safety data -
The safety of omalizumab was studied in cynomolgus monkeys, as omalizumab binds to cynomolgus and human IgE with similar affinity. Antibodies to omalizumab have been found in some monkeys following repeated subcutaneous or intravenous administration. However, no apparent toxicity such as immune complex mediated disease or complement-dependent cytotoxicity was observed. An anaphylactic response due to degranulation of the mast cells in cynomolgus monkeys.
Chronic administration of omalizumab up to doses of 250 mg / kg (at least 14 times the maximum recommended clinical dose in mg / kg according to the recommended dose table) was well tolerated in non-human primates (both adult and juvenile animals), with except for a dose-related and age-dependent decrease in platelet count, with greater sensitivity in juvenile animals. The serum concentration needed to achieve a 50% reduction in platelets from baseline in adult cynomolgus monkeys was approximately 4 to 20 times higher than anticipated maximum clinical serum concentrations In addition, acute haemorrhages and inflammation at the injection sites were observed in cynomolgus monkeys.
No formal carcinogenicity studies have been conducted with omalizumab.
In reproduction studies in cynomolgus monkeys, subcutaneous doses up to 75 mg / kg per week (at least 8 times the maximum recommended clinical dose in mg / kg over a 4-week period) did not cause maternal toxicity, embryotoxicity or teratogenicity when administered. throughout the period of organogenesis and did not cause adverse effects on fetal or neonatal growth when administered during late gestation, delivery and lactation.
Omalizumb is excreted in the breast milk of cynomolgus monkeys. The levels of omalizumab detected in milk were 0.15% of the maternal serum concentration.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Dust
Sucrose
L-histidine
L-histidine hydrochloride monohydrate
Polysorbate 20
Solvent
Water for injections
06.2 Incompatibility "-
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
06.3 Period of validity "-
4 years.
After reconstitution
Chemical and physical stability of the reconstituted medicinal product has been demonstrated for 8 hours at 2 ° C to 8 ° C and for 4 hours at 30 ° 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 - 8 ° C or 2 hours at 25 °. C.
06.4 Special precautions for storage -
Store in a refrigerator (2 ° C - 8 ° C).
Do not freeze.
For storage conditions after reconstitution, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package -
Powder vial: Clear, colorless, type I glass vial with rubber stopper and gray flip-off seal.
Solvent vial: Clear, colorless, type I glass vial containing 2 ml of water for injections.
Carton containing one vial of powder for solution for injection and one ampoule of water for injections.
06.6 Instructions for use and handling -
The lyophilized medicine takes 15-20 minutes to dissolve, although it may sometimes take longer. The fully reconstituted medicine appears clear or slightly opaque and may have small bubbles or foam around the edge of the vial. Due to the viscosity of the reconstituted medicinal product, care should be taken to withdraw all the product from the vial before expelling any excess air or solution from the syringe to obtain 0.6 ml.
To prepare vials of Xolair 75 mg for subcutaneous administration, follow these instructions:
1. Draw 0.9 ml of water for injections from the vial into a syringe equipped with a large 18 gauge needle.
2. With the vial held upright on a flat surface, insert the needle and transfer the water for injections into the vial containing the lyophilized powder, following standard sterile techniques, directing the water for injections directly onto the powder.
3. Holding the vial upright, repeatedly invert vigorously (do not shake) for approximately one minute to evenly moisten the powder.
4. To aid in dissolution, after completing step 3, gently invert the vial for 5-10 seconds, approximately every 5 minutes, to dissolve any remaining solid particles.
It should be noted that in some cases it may take more than 20 minutes for the powder to dissolve completely. If so, repeat step 4 until no more gel-like particles are visible in the solution.
When the medicinal product is completely dissolved, no gel-like particles should be visible in the solution. Small bubbles or foam around the edge of the vial are common. The reconstituted medicine will appear clear or slightly opaque. Do not use if solid particles are present.
5. Invert the vial for at least 15 seconds to allow the solution to flow to the stopper. Using a new 3 mL syringe fitted with a large 18 gauge needle, insert the needle into the upside down vial. Keeping the vial upside down, place the needle tip at the 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 towards the end of the syringe barrel to draw out 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, larger bubbles, and any excess solution in order to obtain the required 0.6 mL solution. A thin layer of small bubbles may remain on top of the solution in the syringe. As the solution is slightly viscous, administration of the solution by injection under the skin may take 5-10 seconds.
The vial delivers 0.6 ml (75 mg) of Xolair.
8. Injections are administered subcutaneously in the deltoid region of the arm or thigh.
Xolair 75 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).
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
UK
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/05/319/001
036892026
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 25 October 2005
Date of most recent renewal: 25 October 2010
10.0 DATE OF REVISION OF THE TEXT -
D.CCE June 2015
