Ultibro Breezhaler capsules with pores for inhalation 50 mcg+110 mcg x30
Ultibro Breezhaler capsules with por d/ingal 50 mcg+110 mcg x30, ATX code: R03AL04 (Indacaterol and glycopyrronium bromide)
Active substances
indacaterol Rec.INN WHO registered glycopyrronium bromide Rec.INN WHO registered
Dosage form
ULTIBRO® BREEZHALER®
caps. with powder for inhalation 50 mcg+100 mcg: 6, 12, 30, 48, 90 or 150 pcs. included with inhalation device (breezhaler) reg. No.: LP-003386 dated 12/28/15 - Valid
Release form, composition and packaging
Capsules with powder for inhalation, hard, size No. 3, transparent, colorless, marked with the “Novartis logo” in black on the cap and the inscription “IGP110.50” in blue ink above the double blue stripe on the body, the contents of the capsules are white or almost white powder .
1 caps.
glycopyrronium base 50 mcg,
which corresponds to glycopyrronium bromide 63 mcg
indacaterol base 110 mcg,
which corresponds to indacaterol maleate 143 mcg
Excipients: lactose monohydrate - 24.757 mg, magnesium stearate - 37 mcg.
Capsule composition: hypromellose - 45.7 mg, water - 2.7 mg, carrageenan - 420 mcg, sodium chloride - 180 mcg. Composition of black ink: shellac, black iron oxide dye (E172), propylene glycol, potassium hydroxide, water. Blue ink composition: shellac, indigo carmine (E132), propylene glycol, titanium dioxide.
Clinical and pharmacological group: Combined bronchodilator - m-cholinergic receptor blocker + beta2-adrenomimetic Pharmaco-therapeutic group: Combined bronchodilator (m-cholinergic blocker + selective beta2-adrenergic agonist)
pharmachologic effect
Combined long-acting bronchodilator drug for inhalation use. Glycopyrronium bromide and indacaterol included in its composition cause relaxation of bronchial smooth muscles, mutually enhancing the bronchodilator effect due to a different mechanism of action.
Glycopyrronium bromide is a long-acting inhaled anticholinergic drug intended for maintenance treatment of bronchial conduction disorders in patients with COPD. Its mechanism of action is based on blocking the bronchoconstrictor effect of acetylcholine on smooth muscle cells of the respiratory tract, which leads to a bronchodilator effect. In the human body, 5 subtypes of muscarinic receptors (M1-5) have been identified. Only subtypes M1-3 are known to be involved in the physiological function of the respiratory system. Glycopyrronium bromide has 4-5 times greater selectivity for receptors of the M1 and M3 subtypes compared to receptors of the M2 subtype. This leads to the rapid onset of a therapeutic effect after inhalation of the drug, which is confirmed by clinical studies.
The bronchodilating effect of glycopyrronium bromide after inhalation lasts more than 24 hours. The duration of action of the drug after inhalation is due to the long-term maintenance of the therapeutic concentration of the drug in the lungs, which is confirmed by a longer T1/2 of the drug after inhalation use, compared to intravenous administration.
Indacaterol is a selective beta2-adrenergic agonist with ultra-long action (within 24 hours with a single dose). The pharmacological action of beta2-agonists, including indacaterol, is associated with stimulation of intracellular adenylate cyclase, an enzyme that catalyzes the conversion of ATP to cyclic 3′,5′-AMP (cAMP). An increase in cAMP content leads to relaxation of bronchial smooth muscles. Indacaterol is an almost complete agonist of β2-adrenergic receptors; the stimulating effect of the drug on β2-adrenergic receptors is 24 times stronger than on β1-adrenergic receptors, and 20 times stronger than on β3-adrenergic receptors. After inhalation, indacaterol has a rapid and long-lasting bronchodilator effect.
Since the density of M3-cholinergic receptors and β2-adrenergic receptors in the central and peripheral airways differs, beta2-agonists are better at relaxing the peripheral airways, while M-anticholinergics have a more significant effect on the central airways. Thus, the combination of an m3-anticholinergic blocker and a beta2-adrenergic agonist promotes optimal expansion of the bronchi throughout the human lower respiratory tract system.
The effect of Ultibro® Breezhaler® occurs within 5 minutes after inhalation and remains at a constant level for 24 hours, providing a lasting significant improvement in lung function: at the 26th week of therapy, an increase in forced expiratory volume in the first second (FEV1) by an average of 320 ml compared with patients receiving placebo, and 110 ml compared with patients receiving glycopyrronium bromide, indacaterol or tiotropium bromide alone. There was also a decrease in functional residual lung capacity and residual lung volume by 350 ml and 380 ml (p <.0.001) compared with placebo 60 minutes after administration on the first day of use and by 520 ml and 520 ml (p <.0.001) by compared with placebo after 21 days of therapy, respectively. When using the drug, there is a decrease in shortness of breath and improved tolerance to physical activity. There is also a significant reduction in the risk of exacerbations of COPD (increasing the time until the next exacerbation), reducing the need for inhaled short-acting beta2-agonists and improving the quality of life of patients (assessed using a certified questionnaire from St. George's Hospital).
Based on clinical studies, it was shown that the drug Ultibro® Breezhaler® in therapeutic and supratherapeutic doses does not have a clinically significant effect on heart rate, QT interval length, potassium content and glucose concentration in the blood serum.
Pharmacokinetics
Suction
Ultibro® Breezhaler®
After inhalation of the drug Ultibro® Breezhaler®, the average time to reach Cmax of glycopyrronium bromide and indacaterol in blood plasma was 15 minutes and 5 minutes, respectively. The AUC of glycopyrronium bromide at steady state when using the drug Ultibro® Breezhaler® corresponds to that when inhaling glycopyrronium bromide alone.
According to an in vitro study that examined the effectiveness of inhalation, the dose of indacaterol delivered to the lungs with Ultibro® Breezhaler® is equivalent to the use of indacaterol alone at a dose of 150 mcg. The AUC of indacaterol at steady state when using the drug Ultibro® Breezhaler® corresponds to or may be slightly lower than that when indacaterol is inhaled separately at a dose of 150 mcg. The absolute bioavailability of indacaterol when using the drug Ultibro® Breezhaler® ranges from 47% to 66%, glycopyrronium bromide - about 40%.
Glycopyrronium bromide
After inhalation, glycopyrronium bromide is rapidly absorbed and reaches Cmax in blood plasma after 5 minutes. About 90% of the systemic exposure of glycopyrronium bromide is due to absorption in the lungs, and 10% is due to absorption in the gastrointestinal tract. The absolute bioavailability of glycopyrronium bromide after inhalation is estimated at 40% of the delivered dose. With regular inhalations (1 time/day), Css glycopyrronium bromide is achieved within 1 week. The AUC of glycopyrronium bromide at steady state was 1.4-1.7 times higher than after the first inhalation. The Cmax of glycopyrronium bromide in the steady state (when inhaled at the recommended dose 1 time/day) and the concentration of glycopyrronium bromide in the blood plasma at the end of the dosing period are 166 pg/ml and 8 pg/ml, respectively.
Indacaterol
The average time to reach Cmax of indacaterol in the blood serum is about 15 minutes after a single or repeated inhalations. Serum concentrations of indacaterol increase with repeated use of the drug. Css of the substance in the blood is achieved within 12-15 days of using the drug. When the drug is inhaled at a dose of 60 to 480 mcg (dose delivered to the lungs) with a frequency of 1 time / day for 14 days, the accumulation coefficient of indacaterol, estimated by the AUC value of the drug on the 1st and 14th or 15th days, ranges from 2.9 to 3.8.
Distribution
Glycopyrronium bromide
After intravenous administration, the volume of distribution in the equilibrium state (Vss) of glycopyrronium bromide was 83 l, the volume of distribution in the terminal phase (Vz) was 376 l. The apparent volume of distribution in the terminal phase after inhalation (Vz/F) was 7310 L, which reflects the slower elimination of the drug after inhalation. In vitro, the binding of glycopyrronium bromide to human plasma proteins is 38-41% at a concentration of 1-10 ng/ml.
Indacaterol
After IV administration, Vz of indacaterol was 2557 L, indicating a significant distribution of the drug. Binding to human plasma proteins in vitro is approximately 95%.
Metabolism
Glycopyrronium bromide
In vitro, it has been noted that hydroxylation of glycopyrronium bromide leads to the formation of various mono- and bi-hydroxylated metabolites, and direct hydrolysis leads to the formation of carboxylic acid derivatives (M9). In vitro studies have shown that CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium bromide. Hydrolysis to M9 appears to be catalyzed by enzymes of the cholinesterase family. Because In vitro studies have not revealed the metabolism of the active substance in the lungs, and M9 makes a minor contribution to the circulation (4% of Cmax and AUC of glycopyrronium bromide) after intravenous administration, it is assumed that M9 is formed from the fraction of the active substance absorbed from the gastrointestinal tract (after inhalation) by presystemic hydrolysis and/or during the “first pass” through the liver. After inhalation or IV administration, only minimal amounts of M9 were detected in the urine (<0.5% of the administered dose). Glucuronic and/or sulfate conjugates of glycopyrronium bromide have been detected in human urine after repeated inhalations at approximately 3% of the delivered dose. In vitro inhibition studies have shown that glycopyrronium bromide does not have a significant ability to inhibit the activity of the isoenzymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the transport proteins MDR1, MRP1 or MXR, which mediate the elimination of drugs from cells, and also transporter proteins OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies have not revealed that glycopyrronium bromide has a clinically significant ability to induce cytochrome P450 isoenzymes, the UGT1A1 enzyme, and the MDR1 and MRP2 transporter proteins.
Indacaterol
When radiolabeled indacaterol is administered orally, unchanged indacaterol is the major serum component and accounts for approximately 1/3 of the drug's daily AUC. Of the metabolites of indacaterol in blood serum, the hydroxylated derivative of indacaterol is determined to the greatest extent. The phenolic O-glucuronide of indacaterol and hydroxylated indacaterol are found in smaller quantities. In addition, diastereomers of the hydroxylated derivative, indacaterol N-glucuronide, and C- and N-dealkylation products were detected.
The UGT1A1 isoenzyme is the only isoenzyme that metabolizes indacaterol to the phenolic O-glucuronide. Hydroxylation of indacaterol occurs mainly via the CYP3A4 isoenzyme. It has also been established that indacaterol is a low-affinity substrate for the membrane transporter of P-glycoprotein (P-gp) molecules.
Removal
Glycopyrronium bromide
Excretion of glycopyrronium bromide by the kidneys reaches 60-70% of total plasma clearance, 30-40% is excreted in other ways - with bile or through metabolism. In healthy volunteers and patients with COPD who received glycopyrronium in doses of 50 to 200 mcg 1 time/day once and repeatedly, the average renal clearance of glycopyrronium ranged from 17.4 to 24.4 l/h. Excretion of glycopyrronium bromide through the kidneys is due to active tubular secretion. Up to 23% of the dose is found unchanged in the urine. The concentration of glycopyrronium bromide in the blood plasma decreases multiphasically. The average terminal T1/2 is longer after inhalation (33-57 hours) than after intravenous (6.2 hours) or oral administration (2.8 hours). The nature of elimination suggests prolonged absorption in the lungs and/or penetration of glycopyrronium bromide into the systemic circulation during and after 24 hours after inhalation.
Indacaterol
The amount of unchanged indacaterol excreted by the kidneys is less than 2.5% of the delivered dose. The renal clearance of indacaterol averaged 0.46-1.2 l/h. Considering that the serum clearance of indacaterol is 18.8-23.3 l/h, it is obvious that excretion of the drug through the kidneys is insignificant (approximately 2-5% of systemic clearance). When taken orally, indacaterol was excreted mainly through the intestines: unchanged (54% of the dose) and in the form of hydroxylated metabolites (23% of the dose).
The concentration of indacaterol in the blood serum decreases multiphasically with a mean final T1/2 ranging from 45.5 to 126 hours. Effective T1/2, calculated based on the accumulation of indacaterol after repeated use, ranged from 40 to 52 hours, which is consistent with the established time to reach equilibrium condition (12-15 days).
The AUC of indacaterol at steady state increased proportionally to the delivered dose, ranging from 120 mcg to 480 mcg.
Linearity/nonlinearity
Glycopyrronium bromide
In patients with COPD, the AUC as well as the total renal excretion of glycopyrronium bromide at steady state increased in a dose-proportional manner ranging from 50 mcg to 200 mcg.
Indacaterol
Systemic exposure of indacaterol increases in proportion to increasing doses (from 150 to 600 mcg). Systemic exposure of the drug is due to its absorption both in the lungs and in the gastrointestinal tract.
Pharmacokinetics in special groups of patients
Ultibro® Breezhaler®
Age, gender and body weight do not have a significant effect on the pharmacokinetics of Ultibro® Breezhaler® in patients with COPD. There was a negative correlation between AUC and lean body mass (or body weight), however, since AUC did not change significantly and the predictive value of lean body mass is low, dosage adjustment based on this parameter is not recommended. Smoking and baseline FEV1 values do not have a visible effect on the AUC of Ultibro® Breezhaler®.
Based on the pharmacokinetic properties of each component used individually, Ultibro® Breezhaler® can be used at the recommended dose in patients with mild to moderate liver dysfunction. There are no data on the use of the drug in patients with severe liver dysfunction.
Based on the pharmacokinetic properties of each component used individually, Ultibro® Breezhaler® can be used at the recommended dose in patients with mild to moderate renal impairment. In patients with severely impaired renal function or end-stage chronic renal failure (ESRD) requiring hemodialysis, Ultibro® Breezhaler® should be used only if the expected benefit outweighs the possible risk.
There was no statistically significant effect of ethnicity on the AUC of both components.
Glycopyrronium bromide
Age and body weight are factors influencing interindividual differences in drug AUC. The recommended dose of glycopyrronium bromide can be safely used in any age group and at any body weight. Gender, smoking, and baseline FEV1 had no apparent effect on the AUC of glycopyrronium bromide.
Clinical studies have not been conducted in patients with liver failure. Elimination of glycopyrronium bromide occurs primarily through renal excretion. Impaired hepatic metabolism of glycopyrronium bromide is not expected to result in a clinically significant increase in AUC.
Renal impairment affects the AUC of glycopyrronium bromide. A moderate increase in AUC of up to 1.4 times was observed in patients with mild to moderate renal failure and up to 2.2 times in patients with severe and end-stage renal failure. The use of a population pharmacokinetic analysis led to the conclusion that in patients with COPD with concomitant mild to moderate renal failure (assessed by GFR > 30 ml/min/1.73 m2), glycopyrronium bromide can be used in recommended doses.
No differences were found between ethnic subgroups.
Indacaterol
Age (adult patients up to 88 years), gender and body weight (32-168 kg) do not affect the pharmacokinetics of indacaterol in patients with COPD.
The pharmacokinetics of indacaterol did not change significantly in patients with mild to moderate hepatic impairment. The use of the drug in patients with severe liver dysfunction has not been studied.
Since indacaterol is excreted by the kidneys to a small extent, the pharmacokinetics of the drug in patients with impaired renal function have not been studied.
No differences were found between ethnic subgroups. Experience with the drug in people of the Black race is limited.
Indications
- long-term maintenance therapy for bronchial obstruction in patients with chronic obstructive pulmonary disease, alleviating symptoms and reducing the number of exacerbations.
ICD-10 codes
Dosage regimen
The drug is a capsule with powder for inhalation, which should only be used for inhalation through the mouth using a special device for inhalation (breezhaler), included in the kit. The drug cannot be taken orally.
Capsules with powder for inhalation should be stored in a blister and removed from it immediately before use.
The recommended dose of Ultibro® Breezhaler® is 110 mcg + 50 mcg (contents of 1 capsule) 1 time/day. Inhalation of the drug is carried out daily at the same time. If a dose is missed, it should be taken as quickly as possible. You should not take more than 1 dose of the drug per day.
When prescribing Ultibro® Breezhaler®, the patient should be instructed on the correct use of the inhalation device.
If there is no improvement in respiratory function, you should make sure that the patient is using the drug correctly. The drug should be inhaled and not swallowed.
No dose adjustment is required in patients aged ≥75 years.
In patients with mild or moderate renal impairment, no dose adjustment is required. In patients with severe or end-stage renal failure requiring hemodialysis, Ultibro® Breezhaler® should be used at the recommended dose only if the expected benefit outweighs the potential risk.
In patients with mild to moderate liver dysfunction, no dose adjustment is required. The use of the drug in patients with severe liver dysfunction has not been studied.
Instructions for use of the inhalation device
Each package of Ultibro® Breezhaler® contains one inhalation device (breezhaler) and blisters of capsules with powder for inhalation.
Capsules with powder for inhalation should not be taken orally.
The inhalation device contained in the package is intended for use only in conjunction with drug capsules.
For inhalation of the capsules in the package, only a breathhaler is used.
The drug capsules should not be used with any other inhalation device and, in turn, the Breezhaler should not be used for inhalation of other drugs.
After 30 days of use, Breezhaler should be thrown away.
Instructions for use of the inhalation device
1. Remove the cover.
2. Open the inhalation device by firmly grasping it by the base and tilting the mouthpiece.
3. Separate one blister from the blister pack by tearing it off along the perforation. Take one blister and remove the protective film from it to release the capsule.
4. Wipe your hands dry and remove the capsule from the blister. The capsule should not be swallowed.
5. Place the capsule in the capsule chamber. Do not place the capsule directly into the mouthpiece.
6. Close the breezehaler tightly. When it closes all the way, you should hear a click.
7. The breathhaler should be held in a vertical position with the mouthpiece pointing upward. Press both buttons all the way down at the same time. When the capsule is pierced, a click should be heard. Do not press the buttons to pierce the capsule more than once.
8. Completely release the breathhaler buttons on both sides.
9. Before inserting the mouthpiece into your mouth, you should exhale completely. Do not blow into the mouthpiece.
10. Place the mouthpiece of the breathhaler in your mouth and press your lips tightly around it. Holding the breathhaler with your hand, take a quick, even, as deep breath as possible. Do not press the buttons on the lancing device.
11. When the patient inhales through the inhalation device, a characteristic rattling sound should be heard, created by the rotation of the capsule in the chamber and spraying of the powder. The patient may feel a sweetish taste of the drug in the mouth. If a rattling sound is not heard, this may mean that the capsule is stuck in the breathhaler chamber. In this case, you should open the breathhaler and carefully release the capsule by knocking on the base of the device. To release the capsule, do not press the buttons to pierce the capsule. If necessary, repeat steps 9 and 10.
12. If the patient hears a characteristic sound when inhaling, it is necessary to hold the breath as long as possible (so as not to experience discomfort), and at the same time remove the mouthpiece from the mouth. After this, exhale. Then you should open the breathhaler and see if there is any powder left in the capsule. If there is any powder left in the capsule, close the breathhaler and repeat steps 9-12. Most people can empty the capsule in 1 or 2 inhalations. Some people experience a cough for a short time after inhaling the drug. If a cough occurs, there is no need to worry. If there is no powder left in the capsule, then the patient has received the full dose of the drug.
13. After taking the daily dose of Ultibro® Breezhaler®, you should tilt the mouthpiece, remove the empty capsule by tapping the inhalation device and throw it away. Lower the breathhaler mouthpiece and close it with the lid. Capsules should not be stored in a breather.
Memo for the patient
Do not swallow capsules containing inhalation powder.
It is necessary to use only the breathhaler contained in the package.
Capsules should be stored in a blister and removed immediately before use.
You should never put a capsule into the mouthpiece of a breathhaler.
Do not press the lancing device more than once.
You should never blow into the mouthpiece of a breathhaler.
The capsule should always be punctured before inhalation.
The breathhaler should not be washed; it must be kept dry.
The breathhaler should not be disassembled.
When starting a new package of the drug, you should always use the new Breezhaler contained in the package for inhalation of capsules.
Capsules should not be stored in a breather.
Blisters with capsules and breathhaler should always be stored in a dry place.
Additional Information
In very rare cases, a small amount of the contents of the capsules may be swallowed. The patient should not worry if he inhaled or swallowed the contents of the capsules.
If the patient punctures the capsule more than once, the risk of it breaking increases.
How to clean the breathhaler
The breathhaler should be cleaned once a week. The mouthpiece is wiped inside and out with a clean, dry cloth. Water should never be used to clean the breathhaler; it must be kept dry.
Side effect
Adverse events when using the drug Ultibro® Breezhaler® are characterized by symptoms typical of m-anticholinergic agents and beta2-adrenergic agonists used in monotherapy. Other most common adverse events associated with this drug (occurring in at least 3% of patients treated with Ultibro® Breezhaler® and at a higher incidence than placebo) include cough and oropharyngeal pain ( including sore throat).
In patients with COPD, when inhaled in recommended doses, the drug does not have a clinically significant systemic beta2-adrenomimetic effect. Heart rate changed on average by no more than 1 beat/min, and tachycardia developed rarely and with less frequency than in the placebo group. The incidence of significant prolongation of the QTc interval (>.450 ms) and hypokalemia was similar to that in the placebo group.
Below are the adverse events that were observed when using the drug during registration clinical studies (lasting 6 and 12 months), the drug was used once a day in patients with COPD. Adverse events are distributed according to frequency of occurrence. The following criteria were used to assess frequency: very often (≥1/10), often (≥1/100, <.1/10), infrequently (≥1/1000, <.1/100), rarely (≥1/10 000, <.1/1000), very rarely (<.1/10,000), including individual messages.
Infectious and parasitic diseases: very often - upper respiratory tract infection, often - nasopharyngitis, urinary tract infection, sinusitis, rhinitis.
From the immune system: rarely - hypersensitivity.
From the side of metabolism: infrequently - diabetes mellitus and hyperglycemia.
Mental disorders: infrequently - insomnia.
From the nervous system: often - dizziness, headache, infrequently - paresthesia.
From the side of the organ of vision: infrequently - glaucoma1.
From the cardiovascular system: infrequently - ischemic heart disease, atrial fibrillation, tachycardia, palpitations.
From the respiratory system: often - cough, pain in the oropharynx, sore throat, infrequently - nosebleeds.
From the digestive system: often - dyspepsia, dental caries, infrequently - dryness of the oral mucosa.
From the skin and subcutaneous tissues: infrequently - rash, itching.
From the musculoskeletal system: often - pain in muscles and bones, infrequently - muscle spasm, myalgia.
From the urinary system: infrequently - bladder obstruction, urinary retention.
Other: often - fever1, chest pain, infrequently - peripheral edema, fatigue.
1 - new adverse events that were observed during the use of the combined drug Ultibro® Breezhaler® and were not observed when using each of the components separately.
The following adverse events were also observed with the use of glycopyrronium bromide or indacaterol as monotherapy.
From the respiratory system: infrequently - paradoxical bronchospasm.
From the digestive system
Onbrez Breezhaler: a new drug in the treatment of chronic obstructive pulmonary disease
Statistics show that COPD affects 210 million people worldwide. In developed and developing countries there is a steady trend towards an increase in the prevalence of COPD. Unlike other diseases, mortality from this disease not only does not decrease, but also shows an increasing trend. According to the European Respiratory Society, only 25% of cases are detected in the early stages. According to experts from the World Health Organization, if urgent measures are not taken to reduce exposure to risk factors, especially to reduce exposure to tobacco smoke, overall mortality from COPD will increase by 30% over the next 10 years. In Russia, the number of registered patients remains at the same level from year to year, which is due to an insufficient level of diagnosis. In 2007, 2.4 million patients with COPD were registered. At the same time, the number of actually sick people is 11 times higher than official data. Approximately every third patient with COPD has a moderate (31%) or mild (29%) severity of the disease, and every fifth has a severe (23%) or very severe (17%) degree. COPD is a pathology that requires continuous lifelong maintenance therapy, without which not only does the frequency of exacerbations increase, the patient’s general condition worsens and his quality of life decreases, but the risk of death also increases significantly. However, practicing physicians are well aware that one of the most serious obstacles to effective treatment of chronic diseases is low patient adherence to treatment and non-compliance with the treatment regimen prescribed by the doctor. Patients with COPD are no exception and, sooner or later, many of them stop regularly taking medications for basic therapy or completely refuse to take them. Is it possible to solve this problem? Currently, one of the most effective ways to increase patient adherence to treatment is to simplify the treatment regimen and, first of all, reduce drug intake to 1 dose per day. Optimal from the point of view of ensuring high patient adherence to therapy is a single dose of the drug per day. Taking this into account, I set myself the task of creating a new b2-agonist, which, when taken once a day, would provide a 24-hour bronchodilator effect, and would also be superior in clinical effectiveness to existing long-acting b2-agonists, characterized by a rapid onset of action (within 5 minutes). , good tolerability and favorable safety profile. As a result, a new ultra-long-acting b2 agonist was developed - indacaterol (commercial name - Onbrez). The indacaterol molecule was created from a modified hydrophilic head group of the formoterol molecule, which ensures its high internal activity, and a lipophilic tail - more rigid, compact and short compared to salmeterol. This made it possible to optimize the hydro- and lipophilic properties of the molecule and ensure, on the one hand, a long duration of action, and on the other, its rapid onset. It should be noted that in terms of the degree of lipophilicity, indacaterol is comparable to salmeterol, but it is characterized by a 2-fold higher affinity for lipid rafts in the membrane, which determines its 24-hour effectiveness. Why does a drug with the same high lipophilicity as salmeterol provide such a rapid onset of action? This is explained by the high intrinsic activity of indacaterol, in other words, it is a full b2 receptor agonist, like formoterol [5,6]. According to the general opinion of experts, indacaterol can be prescribed to patients [1]: • with newly diagnosed COPD and who have not previously taken LABD; • receiving short-acting bronchodilators, ICS and other drugs that do not correspond to their stage of the disease in accordance with the GOLD recommendations; • if the prescription of tiotropium bromide is not effective enough (exacerbations persist, the patient is not satisfied with the quality of the therapy, etc.), and then it is possible to replace tiotropium with indacaterol or add it to the already ongoing treatment. For the first 2 groups, the undoubted advantage will be the speed of onset of the effect, which will increase the adherence and internal motivation of patients to treatment. During the discussion, it was noted that it is important for patients with COPD to be able to take their “first breath” after waking up at night. Based on the results of studies reviewed by the expert council, it was concluded that, despite the same effectiveness of a single morning or evening dose, indacaterol should be recommended to patients in the morning [18]. What doses of indacaterol are used in clinical practice? The recommended dose of indacaterol for patients with COPD is 150 mcg once a day; the Brizhaler capsule metered-dose inhaler is used to deliver the drug into the respiratory tract [2,3,12,16]. For more severe patients with COPD, it is possible to choose a dose of indacaterol 300 mcg (in 1 capsule), since increasing the dose of the drug can provide additional clinical effect [2,3,12,16]. To date, a solid evidence base has been accumulated regarding the effectiveness and safety of indacaterol, and this drug is included in the GOLD recommendations. In total, more than 10 thousand patients with COPD took part in clinical trials studying indacaterol. It has been convincingly shown that indacaterol is significantly superior in effectiveness not only to placebo, but also to other modern bronchodilators for the basic treatment of COPD (salmeterol, formoterol and tiotropium). The results of 4 pivotal clinical trials (INLIGHT 1 [10], INHANCE [9], INVOLVE [8], INLIGHT 2) and several ancillary phase III studies (INDORSE, INPUT, INSURE, B2318, etc.), which included patients with moderate and severe COPD, allowed us to draw the following conclusions: • indacaterol provides significantly more pronounced bronchodilation at the time of taking the next dose of the drug compared to tiotropium, salmeterol and formoterol; • the use of indacaterol in doses of 150 and 300 mcg leads to a significant improvement in the minimum daily (that is, before taking the next dose of the drug) forced expiratory volume in the first second (FEV1) compared with placebo; this improvement was greater than the minimum clinically important difference previously established in the studies; • indacaterol provides 24-hour bronchodilation over a long period (more than 1 year) without loss of effectiveness when repeated doses are used; • indacaterol is equally effective when taken in the morning or evening; • indacaterol is characterized by a rapid onset of action (within 5 minutes), is comparable in the rate of development of the bronchodilator effect to salbutamol and is significantly superior to salmeterol/fluticasone propionate and tiotropium [4]; • indacaterol reduces pulmonary hyperinflation, as evidenced by an increase in inspiratory capacity at rest and during exercise. Improvement in pulmonary function indicators according to spirometry when using indacaterol is reflected in the general condition of the patient and his quality of life: - the drug provides a statistically significant and clinically significant improvement in the total indicator of quality of life according to the St. respiratory questionnaire. George (SGRQ)[4]; – reduces the severity of shortness of breath; – significantly reduces the need for emergency medications; – significantly increases the number of days when patients were able to perform their daily activities, as well as nights without awakenings and days without symptoms [4]; – significantly reduces the frequency of exacerbations of COPD, which are a key risk factor for the development of complications, faster disease progression and death in patients with COPD [15]. Safety profile of indacaterol: no cause for concern. An analysis of the results of all studies of indacaterol showed that the drug was well tolerated and had a favorable safety profile. In terms of the frequency and structure of adverse events (AEs), indacaterol is comparable to tiotropium, salmeterol, formoterol and placebo. The most common AEs were nasopharyngitis, cough, upper respiratory tract infection and headache. The mechanism of cough may be related to the stimulating effect of the drug on cough receptors in the upper/central respiratory tract [16]. In most cases, they are slightly or moderately expressed and, moreover, with continued therapy, they are observed less and less often. The incidence of clinically significant changes in glycemia and hypokalemia, which are considered class side effects of b2-agonists, with indacaterol was comparable to that in the placebo group. Another class effect of b2-agonists is considered to be a negative effect on the cardiovascular system. However, indacaterol has demonstrated a favorable cardiovascular safety profile in patients with COPD, who are usually elderly with concomitant cardiovascular pathology. Thus, changes in the electrocardiogram and changes in blood pressure levels when using indacaterol were not clinically significant and were comparable to the changes that were observed during the use of comparator drugs and placebo. A separate study (B2339) examined the effect of indacaterol on the QT interval in healthy volunteers and did not establish a clinically significant increase in this parameter compared to placebo. The mean change in heart rate was only 1 beat/min, and the rate of tachycardia was comparable to that in the placebo group. The advantages of the new drug Onbrez Breezhaler are not limited only to the unique properties of the active substance. It has long been known that the delivery device plays a very important role in ensuring the effectiveness of COPD treatment. Therefore, I paid special attention to the creation of the inhaler. Breezhaler is a dry powder delivery device that has a number of advantages compared to both traditional metered dose aerosol inhalers (MDIs) and other dry powder inhalers (DPIs) (Fig. 1). Unlike traditional pMDIs, when using the Breezhaler delivery device, coordination of inhalation with pressing the canister is not required, which significantly increases the pulmonary deposition of the active substance and, accordingly, the effectiveness of inhalation. At the same time, Brizhaler is characterized by low resistance to air flow, which distinguishes it from many other SPIs. Thanks to this, Brizhaler can be effectively used by patients with COPD of any severity, even with severe impairment of pulmonary function. In addition, the Breezhaler is a very convenient, intuitive and easy-to-use delivery device. This is important for elderly patients, who make up the vast majority of COPD patients. As part of phase III clinical studies, more than 350 thousand packages of Onbrez Breezhaler were successfully used, with 99.9% of patients being satisfied with this delivery device. An additional advantage of the Breezhaler inhaler is the presence of feedback mechanisms: a click when the capsule is pierced, a buzzing noise during inhalation (rotation of the capsule), a sweet taste in the mouth after inhalation (the drug contains lactose), a transparent capsule (must be empty after inhalation). With their help, the patient can verify that the inhalation is performed correctly. Conclusion Patients with a confirmed diagnosis of COPD who have noticeable disease symptoms despite the use of short-acting bronchodilators (SABAs) should be considered as potential candidates for indacaterol therapy. Indacaterol is an attractive single-dose long-acting b2-agonist (LABA), as it has demonstrated superior efficacy compared to twice-dose LABAs. The most frequently reported adverse event when taking indacaterol is cough, but it is usually regarded as mild and does not require discontinuation of the drug. There is also no data available on the effect of indacaterol therapy on the development of cardiovascular AEs, such as increased heart rate, tachycardia, changes in blood pressure and prolongation of the QT interval. Based on existing data, it can be concluded that indacaterol is an effective and safe bronchodilator for long-term maintenance therapy in patients with COPD. The article was published by order and with the financial support of Novartis Pharma LLC (Russia) in accordance with the internal policies of the company and the current legislation of the Russian Federation. According to the agreement with Novartis Pharma LLC, the authors of the article should not have any agreements or financial agreements related to this article with any third parties, and the article was to be written without outside assistance from any third parties.
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Description of the drug ULTIBRO® BRIZKHAILER®
After inhalation of a drug containing this combination, the average time to reach Cmax of glycopyrronium bromide and indacaterol
in blood plasma were 15 minutes and 5 minutes, respectively.
After inhalation of glycopyrronium
is rapidly absorbed and reaches Cmax in blood plasma after 5 minutes. About 90% of the systemic exposure of glycopyrronium occurs through absorption in the lungs, and 10% through absorption from the gastrointestinal tract. The absolute bioavailability of glycopyrronium after inhalation is estimated at 40% of the delivered dose. With regular inhalations (1 time/day), Css glycopyrronium bromide is achieved within 1 week. Exposure to glycopyrronium at steady state was 1.4-1.7 times higher than after the first inhalation. Cmax of glycopyrronium in the steady state (when inhaled at the recommended dose 1 time/day) and the concentration of glycopyrronium in the blood plasma immediately before taking the next dose are 166 pg/ml and 8 pg/ml, respectively. After IV administration, Vss was 83 l and Vz - 376 l. The apparent volume of distribution in the terminal phase after inhalation (Vz/F) was 7310 L, which reflects its slower elimination after inhalation. In vitro, the binding of glycopyrronium to human plasma proteins is 38-41% at a concentration of 1-10 ng/ml. These concentrations are at least 6 times higher than Cmax at steady state when used at a dose of 50 mcg 1 time/day. In vitro, it has been noted that hydroxylation of glycopyrronium leads to the formation of various mono- and bi-hydroxylated metabolites, and direct hydrolysis leads to the formation of carboxylic acid derivatives (M9). In vitro studies have shown that CYP isoenzymes contribute to the oxidative biotransformation of glycopyrronium. Hydrolysis to M9 appears to be catalyzed by enzymes of the cholinesterase family. Because in vitro studies did not reveal the metabolism of the active substance in the lungs, and the contribution of M9 to the circulation was minimal (4% of Cmax and AUC of glycopyrronium) after intravenous administration, it is assumed that M9 is formed from the fraction of the active substance that entered the gastrointestinal tract after inhalation by presystemic hydrolysis and/or during the “first pass” through the liver. After inhalation or IV administration, only minimal amounts of M9 were detected in the urine (≤0.5% of the administered dose). Glucuronic and/or sulfate conjugates of glycopyrronium have been detected in human urine after repeated inhalations at approximately 3% of the delivered dose. Excretion of glycopyrronium by the kidneys reaches 60-70% of total plasma clearance, 30-40% is excreted in other ways - with bile or through metabolism. In healthy volunteers and patients with COPD who received glycopyrronium in doses of 50 to 200 mcg 1 time/day once and repeatedly, the average renal clearance of glycopyrronium ranged from 17.4 to 24.4 l/h. Excretion of glycopyrronium by the kidneys is due to active tubular secretion. Up to 23% of the dose is found unchanged in the urine. The concentration of glycopyrronium bromide in the blood plasma decreases multiphasically. The average terminal T1/2 is longer after inhalation (33-57 hours) than after intravenous (6.2 hours) or oral administration (2.8 hours). The pattern of elimination suggests prolonged absorption, absorption in the lungs and/or penetration of glycopyrronium into the systemic circulation during and after 24 hours after inhalation. In patients with COPD, systemic exposure as well as steady-state renal excretion of glycopyrronium increased in a dose-proportional manner ranging from 50 mcg to 200 mcg.
Indacaterol.
The average time to reach Cmax of indacaterol in the blood serum is about 15 minutes after a single or repeated inhalations. The concentration of indacaterol in the blood serum increases with repeated use of the drug 1 time per day. Css of the substance in the blood is achieved within 12-15 days of using the drug. When the drug is inhaled at a dose of 60 to 480 mcg (dose delivered to the lungs) with a frequency of 1 time / day for 14 days, the accumulation coefficient of indacaterol, estimated by the AUC value of the drug on the 1st and 14th or 15th days, ranges from 2.9 to 3.8. After intravenous administration, the volume of distribution in the terminal phase (Vz) of indacaterol was 2361-2557 L, indicating a significant distribution of the drug. Binding to human plasma proteins in vitro is approximately 95%. When radiolabeled indacaterol is administered orally, unchanged indacaterol is the major serum component and accounts for approximately 1/3 of the drug's daily AUC. Of the metabolites of indacaterol in blood serum, the hydroxylated derivative of indacaterol is determined to the greatest extent. The phenolic O-glucuronide of indacaterol and hydroxylated indacaterol are found in smaller quantities. In addition, diastereomers of the hydroxylated derivative, indacaterol N-glucuronide, and C- and N-dealkylation products were detected. The UGT1A1 isoenzyme is the only isoenzyme that metabolizes indacaterol to the phenolic O-glucuronide. Hydroxylation of indacaterol occurs mainly via the CYP3A4 isoenzyme. It has also been established that indacaterol is a low-affinity substrate for the membrane transporter of P-glycoprotein (P-gp) molecules. The amount of unchanged indacaterol excreted by the kidneys is less than 2.5% of the delivered dose. The renal clearance of indacaterol averaged 0.46-1.2 l/h. Considering that the serum clearance of indacaterol is 18.8-23.3 l/h, it is obvious that its renal excretion is insignificant (approximately 2-5% of systemic clearance). When taken orally, indacaterol was excreted mainly through the intestines:
- unchanged (54% of the dose) and in the form of hydroxylated metabolites (23% of the dose). The concentration of indacaterol in the blood serum decreases multiphasically with a mean final T1/2 ranging from 45.5 to 126 hours. Effective T1/2, calculated based on the accumulation of indacaterol after repeated use, ranged from 40 to 52 hours, which is consistent with the established time to reach equilibrium condition (12-15 days). The AUC of indacaterol at steady state increased proportionally to the delivered dose, ranging from 120 to 480 mcg. Systemic exposure of indacaterol increases in proportion to increasing doses (from 150 to 600 mcg). Systemic exposure of the drug is due to its absorption both in the lungs and in the gastrointestinal tract.
