Bronchitis-Pharmaxis - instructions for use, doses, side effects, contraindications

Composition of black ink: shellac, ethanol, isopropanol, butanol, propylene glycol, purified water, ammonia solution, concentrated, potassium hydroxide, ferric oxide black oxide (E172).

Description:

Hard gelatin capsules № 3. Body and lid - transparent and almost colorless. There are inscriptions in black ink: on the case - "40 mg", on the lid - "PXS". The contents of the capsule are white or almost white powder.

Pharmacotherapeutic group:Expectorant mucolytic agent

ATX: & nbsp

R.05.C.B.16 Mannitol

B.05.C.X.04 Mannitol

B.05.B.C.01 Mannitol

A.06.A.D.16 Mannitol

Pharmacodynamics:Spray-dried mannitol is administered by means of a special device for inhalation. Inhalation of mannitol is intended to improve pulmonary hygiene by correcting the mucociliary clearance disorder characteristic of cystic fibrosis. Although the exact mechanism of action is unknown, it is assumed that the inhalation administration of mannitol changes the viscoelastic properties of sputum, increases the hydration of the parietal fluid layer and increases mucociliary and cough clearance.

Pharmacokinetics:Suction:
In a study of 18 healthy adult male volunteers using an Aridol inhaler, the absolute bioavailability of mannitol in inhalation compared with intravenous administration was 0.59 ± 0.15.
The rate and degree of absorption of mannitol after inhalation was very close to the rate and degree of absorption after oral administration. Tmax after inhalation was 1.5 ± 0.5 hours.
In a study of 9 patients with cystic fibrosis (6 adults,3 adolescents) with the inhalation of 400 mg of mannitol as a single dose (day 1) and then 2 times a day for 7 days (days 2-7), the pharmacokinetic parameters were the same for adults and adolescents, except for a longer average apparent final half-life in adolescents (day 1 = 7.29 h, day 7: = 6.52 h) compared with adults (day 1 = 6.10 h, day 7 : = 5.42 h). In general, the AUC comparison between day 1 and day 7 demonstrated the independence of pharmacokinetics from time to time, showing linearity at the level of the dose administered in this study.
Metabolism:
Mannitol is metabolized after oral administration (intestinal microflora), but after intravenous administration no significant metabolism is observed. A small percentage of systemically absorbed mannitol is metabolized in the liver with the formation of glycogen and carbon dioxide. Studies conducted on rats, mice and humans showed that mannitol does not have toxic metabolites. The metabolic pathway of inhalation mannitol during pharmacokinetic studies has not been studied.
Distribution:
Lung subsidence studies showed 24.7% of the settling of inhalation mannitol, which confirms its distribution in the target organ. Preclinical toxicological studies show that getting into the lungs mannitol absorbed into the blood; the maximum serum concentration is reached within 1 hour. In pharmacokinetic studies of mannitol in 18 healthy adults, after an intravenous dose of 500 mg, the volume of distribution was 34.3 ± 13.8 liters. Evidence that mannitol accumulates in the body, is not available, so the distribution of inhalation mannitol in pharmacokinetic studies has not been studied.
Excretion:
The cumulative volume of mannitol that fell into the urine over a period of 24 hours was close to that found in urine after inhalation (55%) and oral administration (54%) of mannitol. With intravenous administration mannitol is displayed in practically unchanged form by glomerular filtration. 87% of the dose is excreted in the urine within 24 hours. The average final half-life in adults from serum was about 4-5 hours, from urine about 3.6 hours.

Indications:

Bronhitol-Farmaksis indicated for the treatment of cystic fibrosis (CF) in children over 6 years and adults, in addition to the use of dornase alfa, and in patients who can not tolerate or do not respond to dornase alfa.

Contraindications:

Hypersensitivity to mannitol.

Bronchial hyperreactivity to inhaled mannitol.

Carefully:Asthma, impaired lung function with FEV1 less than 30%; refer to "Special instructions".

Pregnancy and lactation:For mannitol, there are no clinical data on the effect on pregnancy. Reproductive studies of animals with inhaled mannitol were not conducted. However, studies with oral mannitol indicate no teratogenic effects in mice and rats at daily doses up to 1.6 mg / kg and in hamsters when taken in daily doses of 1.2 g / kg.
Due to the fact that the consequences of a possible reaction of hyperreactivity on the mother and / or fetus are unknown, when prescribing Bronchitol-Pharmaxis, pregnant women should be cautious.
It is not known whether the blood is excreted mannitol from the body into the mother's breast milk. Excretion of mannitol into milk in animals has not been studied.The decision to continue (stop) breastfeeding or continue (stop) treatment with the drug Bronchitol-Pharmaxis should be taken taking into account the benefits of breastfeeding for the child and the benefits of treatment with the drug Bronchitol-Pharmaxis for a woman.

Dosing and Administration:Before starting treatment with Bronchitol-Pharmaxis, all patients should undergo an assessment for bronchial hyperreactivity to inhaled mannitol when receiving an initial dose (see Contraindications). Patients who have spirometry contraindicated and who for this reason can not be evaluated at the initial dose should not receive Bronchitis-Pharmaxis.
Estimated when taking the initial dose:
The patient should take the initial dose of Bronchitol-Pharmaxis (400 mg) under the supervision and supervision of an experienced physician or other qualified medical professional who has the equipment to monitor the oxygen saturation of the hemoglobin (SpO2), perform spirometry and remove acute bronchospasm. The patient should first receive a bronchodilator drug 5-15 minutes before the initial dose (but after measuring the initial volume of forced expirationfor the first second (FEV1) and SpO2). All measurements of FEV1 and SpO2 control are performed 60 seconds after the inhalation of the dose.
Evaluation when taking the initial dose is carried out in stages:
Step 1: The patient's FEV1 and SpO2 are measured prior to taking the initial dose.
Stage 2: the patient inhales 40 mg (1 capsule 40 mg), followed by SpO2 control.
Stage 3: the patient inhales 80 mg (2 capsules 40 mg), followed by SpO2 control.
Stage 4: the patient inhales 120 mg (3 capsules 40 mg), followed by measurement of FEV1 and control of SpO2.
Step 5: the patient inhales 160 mg (4 capsules of 40 mg), followed by measurement of FEV1 and control of SpO2.
Step 6: The FEV1 of the patient is measured 15 minutes after the initial dose.
During the evaluation of the initial dose, it is important to teach the patient the correct technique for using the inhaler.
Each capsule is inserted into the device separately. The contents of the capsule are inhaled by inhalator in one or two breaths. After inhalation, the empty capsule is discarded, after which the next capsule is inserted into the inhaler.
A patient who has a hyperreactivity in mannitol, should not receive therapeutic doses under any of the following conditions:
- ≥ 10% percentage drop in SpO2 at any point during the evaluation;
- a fall in FEV1 ≥ 20% with a total dose of 240 mg;
- FEV1 fall ≥20% (compared to baseline) at the end of the assessment and no recovery to <20% of baseline within 15 minutes.
Therapeutic dose regimen:
The therapeutic dose regimen should not be administered prior to the assessment when taking the initial dose.
The recommended dosage of Bronchitol-Pharmaxis is 400 mg 2 times a day. This requires the inhalation of 10 capsules 40 mg with an inhaler 2 times a day. Each capsule provides a dose of about 32 mg. Doses should be taken in the morning and in the evening 2-3 hours before bedtime.
The inhaler should be replaced after 1 week of use. If the inhaler requires cleaning, make sure that there are no capsules in it, then rinse with warm water and allow to dry completely in the air before the next use.
For 5-15 minutes before taking Bronchitol-Pharmaxis, the patient should receive a bronchodilator. Recommended course of action: bronchodilator, Bronchitol-Pharmaxis, physiotherapy / exercises, then dornase-alpha (if applicable).

Side effects:In the DPM-CF-301 study, participants in the group receiving mannitol, received the study drug from 1 to 218 days with an average exposure time (SP) of 135.5 (70.09) days. The duration of exposure in the adolescent and children's subgroups was 145.7 (64.58) and 136.2 (69.24) days, respectively.
In total, 822 adverse events (AEs) were registered in 154 (87.0%) patients in the group receiving mannitol, and 541 AE in 109 (92.4%) patients in the control group. 72 (40.7%) participants in the group receiving treatment reported on AEs mannitol, and 26 (22.0%) participants in the control group. Hemoptysis, cough, pain in the pharyngolaryngeal area, toothache, vomiting and diarrhea were more frequent in the group receiving mannitol.
In the DPM-CF-301,28 study (15.8%) in the group receiving mannitol, and 10 (8.5%) of participants in the control group withdrew from the study due to AE. The most frequently observed AEs leading to cessation of participation: cough, deterioration and hemoptysis.
Table. 1: The most frequently observed adverse events associated with treatment in terms of the preferred use of the Medical Regulatory Dictionary (MedDRA) ≥ 2.0% in any major group during the blind study period

The term preferred use	Mannitol [N = 177] n (%)	Control drug [N = 118] n (%)
Deterioration state of	57 (32,2)	42 (35,6)
Cough	45 (25,4)	24 (20,3)
Headache	38 (21,5)	28 (23,7)
Infected sputum	33 (18,6)	22 (18,6)
Nasopharyngitis	25 (14,1)	17 (14,4)
Lower respiratory tract infections	15 (8,5)	20 (16,9)
Hemoptysis	21 (11,9)	10 (8,5)
Pain in the pharyngolaryngeal region	24 (13,6)	5 (4,2)
Upper respiratory tract infections	14 (7,9)	8 (6,8)
Pain in the upper abdomen	12 (6,8)	7 (5,9)
Arthralgia	12 (6,8)	7 (5,9)
Moist cough	12 (6,8)	7 (5,9)
Vomiting	13 (7,3)	4 (3,4)
Backache	7 (4,0)	7 (5,9)
Abdominal pain	6 (3,4)	8 (6,8)
Toothache	9(5,1)	3 (2,5)
Constipation	6 (3,4)	5 (4,2)
Diarrhea	9 (5,1)	1 (0,8)
Temperature increase	7 (4,0)	2 (1,7)
Positive test for fungus in sputum	6 (3,4)	3 (2,5)
Ear ache	5 (2,8)	4 (3,4)
Nausea	4 (2,3)	5 (4,2)
Feeling of discomfort in the chest area	6 (3,4)	2 (1,7)
Tonsillitis	6 (3,4)	2 (1,7)
Pexcessive fatigue	5 (2,8)	3 (2,5)
Nasal congestion	4 (2,3)	4 (3,4)
Chryps	4 (2,3)	4 (3,4)
Nose bleed	5 (2,8)	2 (1,7)
Musculoskeletal pain in the chest	5 (2,8)	2 (1,7)
Rash	4 (2,3)	3 (2,5)
Viral infections	3 (1,7)	3 (2,5)
Bad feeling	3 (1,7)	3 (2,5)
Candidiasis of the mouth	4 (2,3)	2 (1,7)
Pain in the extremities	4 (2,3)	2 (1,7)
Rhinorrhea	4 (2,3)	2 (1,7)
Asthma	2 (1,1)	3 (2,5)
Trip-like state	4 (2,3)	1 (0,8)
Insomnia	4 (2,3)	1 (0,8)
Musculoskeletal pain	4 (2,3)	1 (0,8)
Headache in the area of the paranasal sinuses	4 (2,3)	1 (0,8)
Chest pain	1 (0,6)	3 (2,5)
Feeling of discomfort in the stomach	1 (0,6)	3 (2,5)
Viral infections of the upper respiratory tract	0 (0,0)	4 (3,4)
Allergic rhinitis	0 (0,0)	3 (2,5)

Estimated when taking the initial dose:
The most frequently observed adverse reaction associated with taking Bronchitol-Pharmaxis in the course of the initial dose is coughing.Clinically, the most important adverse reaction during the evaluation when taking the initial dose associated with taking Bronchitol-Pharmaxis is bronchospasm.
Table 2 shows only the side reactions, which can be reasonably established causality with drug treatment of the drug. The incidence is based on observations on the day of screening before the start of a key comparative clinical study examining the effect of Bronchitol-Pharmaxis as an adjunct to current therapy in patients with cystic fibrosis.
The frequency is defined as follows: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (> 1/10 000 up to <1/1000), very rarely (<1/10 000); It is not known (estimation based on available data is not possible). In each frequency group, undesirable phenomena are presented in descending order of severity.
Table. 2: Incidence of adverse reactions with Bronchitol-Pharmaxis on the day of screening

Classification of undesirable reactions (phenomena)	Often	Often	Infrequently
Disorders from the metabolism and nutrition			Dehydration
Disturbances from the respiratory system		Cough	Bronchospasm
Infringements from digestive systems			Pain in the upper abdomen, Vomiting, Vomiting after a fit of severe cough
Laboratory indicators			Increase in the level of alkaline phosphates in the blood.

Therapeutic dose regimen:
It is expected that most patients taking Bronchitis-Pharmaxis may experience side effects. The most commonly observed adverse reaction associated with taking Bronchitol-Pharmaxis is a cough. Clinically, the most important adverse reaction associated with taking Bronchitol-Pharmaxis is hemoptysis.
Table 3 shows only the side reactions, which can be reasonably established causality with drug treatment of the drug. The incidence is based on observations during a key comparative clinical study examining the effect of Bronchitol-Pharmaxis as an adjunct to current therapy in patients with cystic fibrosis.
The frequency of occurrence is determined in the same way as described in Table. 2.
Table.3: Incidence of adverse reactions with Bronchitol-Pharmaxis during the main phase

Classification of undesirable reactions (phenomena)	Often	Often	Infrequently
Infectious and parasitic diseases			Candidiasis of the mouth * Staphylococcal infection
Disorders from the metabolism and nutrition		Decreased appetite
Disturbances from the nervous system		Headache	Dizziness
Disturbances from the organs of hearing and balance			Ear ache
Disturbances from the respiratory system, chest and mediastinal organs	Cough	Hemoptysis Bronchospasm Chryps * Asthma* Deterioration of the condition Pain in the pharyngolaryngeal area Wet cough Sensation discomfort in the chest area Infected sputum *	PPositive test for fungus in sputum Syndrome of swamping of the respiratory tract Stimulation of the throat * Rinorrhea
Infringements from gastrointestinal tract		Vomiting After coughing up vomiting	Gastroesophageal reflux disease Glossalgia
Disturbances from the skin and subcutaneous tissues			Acne Itching Rash Cold sweat

Disturbances from musculoskeletal and connective tissue

Artralgia

Stiffness in the joint Musculoskeletal pain in the chest area

Disorders from the kidneys and urinary tract

Notholding the urine

General disorders and disorders at the site of administration

Pain in the area of the hernial sac

Acne

* The frequency of the adverse reaction is lower than in the control group.
Hemoplegia:
In connection with hemoptysis, 5 participants in the study in the mannitol group withdrew from the study (none of the participants in the study in the control group did not stop participating for this reason). Hemoptysis was more common as a serious AE in the mannitol group (6 (3.4%) participants compared with 2 (1.7%) in the control group). However, the proportion of patients who reported hemoptysis as an AE or hemoptysis when exacerbated was 15.8% in the mannitol group and 15.3% in the control group.
Cough:
Cough is an extremely common AE. Although moist cough has been indicated as a common AE, it is useful in cleansing from phlegm.

Overdose:

There have been no cases of overdose in clinical trials. In susceptible patients with an overdose, bronchospasm may occur.If an excessive cough and bronchospasm occurs, a β2 agonist should be used and, if necessary, oxygen.

Interaction:

Bronchitol-Pharmaxis has been used effectively and safely in clinical studies in combination with standard drugs for cystic fibrosis, such as mucolytics, antibiotics, bronchodilators, pancreatic enzymes, vitamins, inhaled and systemic corticosteroids and analgesics. However, official studies of interactions with other drugs have not been conducted.

Special instructions:Asthma:
Patients with asthma should be carefully monitored for the absence of worsening signs and symptoms of asthma after taking the initial dose of Bronchitol-Pharmaxis. Patients should be informed of the need to report deterioration of symptoms and a symptom of asthma to their healthcare provider.
Hypersensitivity to mannitol:
Patients should be monitored for the absence of bronchial hyperreactivity to inhaled mannitol when evaluated during the intake of the initial dose prior to the initiation of Bronchitol-Pharmaxis at therapeutic doses.If the patient exhibits hyperreactivity, Bronchitol-Pharmaxis should not be prescribed in therapeutic doses. When controlling bronchial hyperreactivity, the usual precautionary measures are used.
Bronchitis-Pharmaxis may cause bronchospasm requiring treatment, even in patients who have not shown hyperreactivity to the initial dose of inhalation mannitol.
Impairment of lung function:
Safety and efficacy have not yet been demonstrated in patients with FEV1 less than 30% of that predicted.
Impaired renal / hepatic function:
Official studies of Bronchitol-Pharmaxis in patients with impaired renal / hepatic function were not performed. There are no specific recommendations for doses for these patient groups.
Hemoplegia:
The condition of patients with significant episodes of hemoptysis in the anamnesis (> 60 mL) should be carefully monitored. Official studies of the drug Bronchitol-Pharmaxis in patients with hemoptysis during the previous 6 months were not conducted. Refer to the "Side effect" section.
Impact on fertility:
The effect of inhalation mannitol on fertility was not investigated.
Admission in children
Bronchitis-Pharmaxis is recommended for use in children under the age of 6 due to insufficient safety and efficacy data.
Admission in the elderly:
In phase II and III studies, the average age of the patients was about 20 years. The age of the oldest patient in Phase II study was 56 years. Specific recommendations for doses for use in the elderly are not available.
Carcinogenicity:
Evidence of carcinogenicity in the study of mice and rats for 2 years with the introduction of mannitol (≤ 5%) in food was not obtained. Carcinogenicity studies with inhaled mannitol have not been conducted.
Genetic toxicity:
In the analysis of mannitol in a standard series of tests for genetic toxicity, mutagenic and clastogenic effects were not identified.
Impact on laboratory data:
Influence on hematologic indices, biochemical indicator of liver function, parameters of blood urea and level of electrolytes were not observed.

Effect on the ability to drive transp. cf. and fur:

There was no adverse effect on the ability to drive and work with machinery when taking the drug Bronchitis-Pharmaxis.

Form release / dosage:

Powder for inhalation dosed, 40 mg.

Packaging:For 10 capsules in a contour mesh packaging of a three-layer film of PA / aluminum / PVC and aluminum foil.
1 contour pack together with the inhaler and instructions for use is placed in a cardboard box.
For 28 contour mesh packages together with 2 inhalers and instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003852

Date of registration:21.09.2016

Expiration Date:21.09.2021

The owner of the registration certificate:Pharmaxis Co., Ltd.Pharmaxis Co., Ltd. Australia

Manufacturer: & nbsp

Pharmaxis Ltd. Australia

Representation: & nbspInstitute of Longevity DNA-L, LLCInstitute of Longevity DNA-L, LLCRussia

Information update date: & nbsp07.03.2017

Illustrated instructions

Instructions

Bronchitol-Pharmaxis (Bronchitol-Pharmaxis)