BUDIFOR PLUS [Budesonide + Formoterol Fumarate] 400 + 12 mcg Hard Capsules for Oral Inhalation
instructions
for the medical use of the medicinal product
BUDIFOR PLUS
Tradename
Budifor plus, Будифор плюс
International non-proprietary name or generic name
Budesonide + Formoterol, Будесонид +
Формотерол
Dosage form
Nasal metered dose spray.
Composition per 1 capsule (inhalation dose):
active
substance: budesonide 400 mcg, formoterol fumarate dehydrate 12 mcg;
excipients: lactose monohydrate, hypromellose.
Combined bronchodilator (selective
beta-2-adrenergic agonist + local glucocorticosteroid).
АТХ code: R03AK07
Pharmacodynamics
Combined bronchodilator. Formoterol
and budesonide have different mechanisms of action and exhibit an additive
effect in reducing the frequency of exacerbations of bronchial asthma and COPD.
The special properties of formoterol and budesonide make it possible to use
their combination simultaneously as maintenance therapy and for stopping
attacks, or as maintenance therapy for bronchial asthma.
Formoterol is a selective beta-2-adrenergic receptor agonist, which after
inhalation causes rapid and prolonged relaxation of bronchial smooth muscles in
patients with reversible airway obstruction. The bronchodilator dose-dependent
effect occurs quickly, within 1-3 minutes after inhalation and lasts for at
least 12 hours after a single dose.
Budesonide is a glucocorticosteroid (GCS) that, after inhalation, has a rapid
(within a few hours) and dose-dependent anti-inflammatory effect on the
respiratory tract, reducing the severity of symptoms and the frequency of
exacerbations of bronchial asthma. When prescribing inhaled budesonide, a lower
incidence of serious adverse effects is noted than when using systemic GCS.
Reduces the severity
of bronchial mucosal edema,
mucus production, sputum formation and airway hyperreactivity. The exact
mechanism of the anti-inflammatory action of GCS is unknown.
The addition of formoterol
to budesonide reduces the severity of bronchial asthma symptoms, improves
bronchial function and reduces the frequency of exacerbations of the disease.
The effect of this fixed combination on bronchial function corresponds to the
effect of a combination of budesonide and formoterol monodrugs and exceeds the
effect of budesonide alone. In all cases, a short-acting beta-2-adrenergic
agonist was used to stop attacks. No decrease in anti-asthmatic effect was
observed over time. The combination is well tolerated.
There is no evidence of a
pharmacokinetic interaction between formoterol and budesonide. The
pharmacokinetic parameters for the corresponding substances are comparable
after administration of formoterol and budesonide as monodrugs and in this
combination. When administered in combination, the AUC of budesonide is
slightly higher, absorption is faster and the Cmax value in blood plasma is
higher. Cmax in blood plasma of formoterol when administered in combination
coincides with that for the monodrug.
Inhaled formoterol is
rapidly absorbed and reaches Cmax in blood plasma 10 minutes after inhalation.
The average dose of formoterol reaching the lungs after inhalation is 28-49% of
the delivered dose. Systemic bioavailability is about 61% of the delivered
dose.
Inhaled budesonide is
rapidly absorbed and reaches Cmax in plasma 30 minutes after inhalation. The
average dose of budesonide that reaches the lungs after inhalation is 32-44% of
the delivered dose. Systemic bioavailability is approximately 49% of the
delivered dose. Plasma protein binding of formoterol is 50%, budesonide - 90%.
Vd of formoterol is about 4 l/kg, budesonide - 3 l/kg.
Formoterol is inactivated
by conjugation (active O-demethylated metabolites are formed, mainly in the
form of inactivated conjugates).
Budesonide undergoes
intensive biotransformation (about 90%) during the "first pass"
through the liver with the formation of metabolites with low glucocorticoid
activity. The glucocorticoid activity of the main metabolites 6-β-hydroxybudesonide and 16-α-hydroxyprednisolone does not exceed 1% of the similar activity of
budesonide. There is no evidence of interaction of metabolites or substitution
reaction between budesonide and formoterol.
The main part of the
formoterol dose is metabolized in the liver and then excreted by the kidneys.
After inhalation, 8-13% of the delivered dose of formoterol is excreted
unchanged in the urine. Formoterol has a high systemic clearance (approximately
1.4 l / min); T1 / 2 of the drug is on average 17 hours.
Budesonide is metabolized
mainly with the participation of the enzyme CYP3A4. Budesonide metabolites are
excreted in the urine unchanged or as conjugates. Only a small amount of
unchanged budesonide is detected in the urine. Budesonide has a high systemic
clearance (approximately 1.2 L/min).
Indications
for use
Bronchial asthma,
inadequately controlled by inhaled corticosteroids and short-acting
beta-2-adrenergic agonists or adequately controlled by inhaled corticosteroids
and long-acting beta-2-adrenergic agonists.
Symptomatic therapy of
patients with severe COPD (FEV1 <50% of predicted calculated level) and with
a history of recurrent exacerbations, who have significant symptoms despite
therapy with long-acting bronchodilators.
Hypersensitivity to the active substances or
excipients; childhood.
Method
of administration and dosage
Inhalation.
Adults (including the
elderly). Recommended doses.
Bronchial
asthma: 1 inhalation 2 times a day; some patients may
require 2 inhalations 2 times a day.
Prevention of
exercise-induced bronchospasm:
1 inhalation approximately
15 minutes before exercise.
COPD: 1 inhalation
2 times a day.
Using Budifor
Plus consists of three steps: open the mouthpiece, inhale
deeply and close the mouthpiece.
To minimize the risk of
oropharyngeal candidiasis, it is recommended to rinse the mouth after
inhalation.
Special
instructions and precautions
Before
using the drug, consult a doctor.
Before
stopping treatment, it is recommended to gradually reduce the dose. It is not
recommended to abruptly stop treatment.
The
combination of formoterol + budesonide is not used for the initial selection of
therapy in the early stages of treatment of bronchial asthma.
Taking
formoterol can cause prolongation of the QT interval.
An
increase in the frequency of taking bronchodilators as emergency drugs
indicates a worsening of the underlying disease and serves as a basis for
revising the tactics of treating bronchial asthma. Unexpected and progressive
deterioration in the control of symptoms of bronchial asthma or COPD is a
potentially life-threatening condition and requires urgent medical
intervention. In this situation, it is necessary to consider increasing the
dose of GCS or adding systemic anti-inflammatory therapy, for example, a course
of oral GCS or antibiotic treatment in case of infection. Patients are advised
to always have emergency drugs (short-acting beta-2-adrenergic agonists) with
them.
The
patient should be advised to regularly take the formoterol+budesonide
combination in accordance with the selected dose, even in cases of asymptomatic
disease.
Treatment
should not be initiated during periods of exacerbation or significant worsening
of asthma.
As with
any other inhalation therapy, paradoxical bronchospasm with immediate increase
in wheezing after taking a dose of the combination drug may occur. In this
regard, therapy should be discontinued, treatment tactics should be reviewed
and, if necessary, alternative therapy should be prescribed.
Systemic
effects may occur with any inhaled GCS, especially when taking drugs in high
doses over a long period of time. The occurrence of systemic effects is less
likely with inhalation therapy than with oral GCS. Possible systemic effects
include adrenal suppression, decreased bone mineral density, cataracts and
glaucoma. Because of the potential effect of inhaled corticosteroids on bone
mineral density, special care should be taken in patients receiving high doses
of the drug for a long period and in the presence of risk factors for
osteoporosis.
If there
is reason to believe that adrenal function has been impaired due to previous
systemic corticosteroid therapy, caution should be taken when transferring
patients to treatment with a combination of formoterol and budesonide.
The need
for the use and dose of inhaled corticosteroids should be reconsidered in
patients with active or inactive forms of pulmonary tuberculosis, fungal, viral
or bacterial respiratory infections.
When
beta-2-adrenergic agonists are co-administered with drugs that can cause or
enhance the hypokalemic effect, such as xanthine derivatives, steroids or
diuretics, the hypokalemic effect of beta-2-adrenergic agonists may be
enhanced.
Special
precautions should be taken in patients with unstable bronchial asthma who are
using short-acting bronchodilators to relieve attacks during exacerbations of
severe bronchial asthma, since the risk of hypokalemia increases against the
background of hypoxia and other conditions that increase the likelihood of
developing a hypokalemic effect. In such cases, it is recommended to monitor
the serum potassium content. Blood glucose concentrations should be monitored
during treatment in patients with diabetes mellitus.
Influence on the ability to drive vehicles and mechanisms
The combination of
formoterol + budesonide may have a minor effect on the occurrence of side
effects. Caution is required when driving vehicles and operating machinery
during treatment.
Use during pregnancy and breastfeeding
During pregnancy, the
combination of formoterol + budesonide should be used only in cases where the
expected benefit of therapy for the mother outweighs the potential risk to the fetus.
Budesonide should be used in the minimum effective dose necessary to maintain
adequate control of asthma symptoms. Inhaled budesonide is excreted in breast
milk, but when used in therapeutic doses, no effect on the child has been
noted. It is unknown whether formoterol is excreted in breast milk in women.
The combination of formoterol + budesonide can be prescribed to nursing women
only if the expected benefit to the mother outweighs any possible risk to the
child.
From the
nervous system: headache, psychomotor agitation, anxiety,
nausea, dizziness, sleep disorders, depression, taste disturbances.
From the
cardiovascular system: palpitations, tachycardia, atrial
fibrillation, supraventricular tachycardia, extrasystole, angina pectoris,
blood pressure fluctuations.
From the
musculoskeletal system: tremor, muscle cramps.
From the
respiratory system: candidiasis of the oral mucosa and pharynx,
mild irritation in the throat, cough, hoarseness, bronchospasm.
Dermatological
reactions: bruising, exanthema, itching, dermatitis.
Allergic
reactions: urticaria, angioedema, anaphylactic
reactions.
Metabolic
disorders: hypokalemia, hyperglycemia, symptoms of
systemic action of GCS (including adrenal hypofunction).
Systemic
action of inhaled GCS can be observed when taking the drug in high doses for a
long time. The use of beta-2-adrenergic agonists can lead to an increase in the
content of insulin, free fatty acids, glycerol, ketone derivatives in the
blood.
If any of the
side effects listed in the instructions worsen, or you notice any other side
effects not listed in the instructions, tell your doctor.
Interaction
with other medicinal products
Ketoconazole 200 mg once
daily increases the plasma concentration of orally administered budesonide
(single dose 3 mg) by an average of 6 times when co-administered. When
ketoconazole was administered 12 hours after budesonide, the plasma
concentration of budesonide increased by an average of 3 times. There is no
information on such an interaction with budesonide when administered by
inhalation; however, a significant increase in plasma drug concentrations
should be expected. Since there are no data to recommend dose adjustments, the
above combination of drugs should be avoided. If possible, the time intervals
between administration of ketoconazole and budesonide should be maximally
increased. A reduction in the budesonide dose should also be considered. Other
potent CYP3A4 inhibitors may also significantly increase plasma concentrations
of budesonide. Beta-2-adrenergic receptor blockers may reduce the intensity of
formoterol action. The combination of formoterol + budesonide should not be
administered simultaneously with beta-blockers (including eye drops), except in
urgent cases. The combined use of formoterol + budesonide and quinidine,
disopyramide, procainamide, phenothiazines, antihistamines (terfenadine), MAO
inhibitors, tricyclic antidepressants can prolong the QT interval and increase
the risk of ventricular arrhythmias. In addition, levodopa, levothyroxine,
oxytocin and alcohol can reduce the tolerance of the heart muscle to
beta-2-adrenergic agonists. The simultaneous use of MAO inhibitors, as well as
drugs with similar properties, such as furazolidone and procarbazine, can cause
an increase in blood pressure. There is an increased risk of arrhythmias in
patients undergoing general anesthesia with halogenated hydrocarbons. With the
simultaneous use of the combination of budesonide + formoterol and other
beta-adrenergic drugs, the side effects of formoterol may be enhanced. As a
result of the use of beta-2-adrenergic agonists, hypokalemia may develop, which
may be enhanced by concomitant treatment with xanthine derivatives, GCS or
diuretics. Hypokalemia may increase the predisposition to the development of
arrhythmias in patients taking cardiac glycosides.
Overdose of
the drug Budifor Plus will be accompanied by symptoms usually observed with
overdose of beta-2-adrenergic receptors: nausea, vomiting, headaches, tremor,
drowsiness, palpitations, tachycardia, ventricular arrhythmias,
increased/decreased blood pressure, prolongation of the QT interval,
hypokalemia, hyperglycemia. Supportive and symptomatic therapy is indicated.
Store in a
dry place at a temperature not exceeding 25°C. Keep out of reach of children.
2 years.
Do not use after expiration date.
Dispensed by prescription.
10 hard capsules for inhalation in an aluminum foil blister. 6 blisters and an inhaler together with instructions for use in a cardboard box.