Salbutamol is a direct-acting sympathomimetic agent which demonstrates relatively selective action on beta-2 adrenergic receptors. Beclometasone dipropionate is a synthetic glucocorticoid with a potent anti-inflammatory activity and weak mineralocorticoid activity. This combination of salbutamol and Beclometasone dipropionate is specially provided for those patients who require regular doses of both drugs for treatment of their obstructive airways disease.
Each actuation delivers: Salbutamol Sulfate, BP equivalent to Salbutamol 100 mcg, Beclometasone Dipropionate Anhydrous 50 mcg.
Excipients: Ethanol BP 3.5 % w/w (5.23 % v/v), Oleic Acid USP NF, Propellant 1,1,1,2-Tetrafluoroethane (HFA 134a).
Pharmacology: Pharmacodynamics: Salbutamol + Beclometasone dipropionate (Ibicar S) is a combination of a bronchodilator, salbutamol, with a topical corticosteroid, beclomethasone dipropionate. Salbutamol is characterized by a rapid and safe anti-spasmodic bronchial action that determines an immediate improvement of respiratory function. The action of salbutamol occurs effectively in the bronchial muscles, without causing undesirable cardiocirculatory effect.
Beclomethasone dipropionate controls the bronchial hyper-activity, reducing edema and hypersecretion, progressively inhibiting the onset of bronchospasm. Therefore, the two active principles complement and potentiate.
The activity of beclomethasone dipropionate is predominantly within the lungs without causing systemic effects such as inhibition of the adrenal functions. In order to obtain successful treatment, it is important that patients carefully follow the instruction of use and learn to inhale the medicine correctly.
Clinical Study: In a Phase III, randomized, open label, non-inferiority, comparative, multicentric, parallel group study of 10 days of treatment period Salbutamol and Beclometasone pressurized inhalation CFC free 100+50 mcg/actuation was compared with HFA propelled pMDI Salbutamol 100 mcg + Beclometasone 50 mcg (ClenilCompositum HFA spray) in patients with stable persistent asthma. Out of a total of 280 subjects, 140 subjects (mean age of 39.22 years) were randomized to Salbutamol and Beclometasone pressurized inhalation CFC free 100+50 mcg/actuation and 140 subjects (mean age of 38.85 years) were randomized to ClenilCompositum HFA spray group. All subjects were Asian with 60% male and 40% female.
The results of the study showed that for the primary efficacy endpoint Forced expiratory volume in one second (FEV1) absolute value was comparable between Salbutamol and Beclometasone pressurized inhalation CFC free 100+50 mcg/actuation and ClenilCompositum HFA spray in patients with stable persistent asthma.
The lower limit of the 95% confidence interval for the difference in FEV1 between groups was greater than the non-inferiority margin of -15% (on negative scale) of adjusted mean FEV1 of ClenilCompositum HFA spray in per protocol (PP) and intent to treat (ITT) population.
Adverse events were reported for 5.0% (7/140) patients in Salbutamol and Beclometasone pressurized inhalation CFC free 100+50 mcg/actuation group and 2.1% (3/140) patients in the ClenilCompositum HFA spray group.
All the adverse events were mild in severity in both treatment groups, there were no severe or moderate AEs reported in the study.
Most of the AEs reported in this study were assessed by the investigator as not related to study drug. Adverse events considered to be related to study medication were reported for 1.4% (2/140) [wheezing and eosinophilia] of patients in Salbutamol and Beclometasone pressurized inhalation CFC free 100+50 mcg/actuation group. Salbutamol and Beclometasone pressurized inhalation CFC free 100+50 mcg/actuation was permanently withdrawn in subjects who experienced an adverse event of wheezing.
There were no clinically significant changes observed from baseline to end of treatment in clinical laboratory evaluations, vital signs, ECG and physical examinations.
There were no serious adverse events, deaths or unexpected safety findings or unexpected AEs reported during the study.
The study concluded that Salbutamol and Beclometasone pressurized inhalation CFC free 100+50 mcg/actuation was safe, well tolerated and non-inferior in efficacy compared to ClenilCompositum HFA spray.
Pharmacokinetics: After inhalation of salbutamol (0.04 to 0.10 mg), the peak plasma appears around 3 to 5 hours. About 83% of the inhaled dose is excreted in urine, 70% in the form of salbutamol and 30% as its metabolite salbutamol-o-phenyl-glucuronide. Kinetic studies showed that after an inhalation of a high dose of beclomethasone, only 20 to 25% of the drug is absorbed. One part of the dose is swallowed and excreted in the feces and the amount absorbed into the circulation is metabolized by the liver to alcohol and beclomethasone monopropionate and subsequently excreted as inactive metabolites in the bile and urine.
Salbutamol + Beclometasone dipropionate (Ibicar S) due to the presence of active salbutamol, has rapid onset of action, within 3 to 5 minutes, which lasts on average 4 hours. In turn, the effects related to beclomethasone dipropionate are manifested in a longer term (1-2 weeks) after initiation of treatment, with significant action on the inflammatory process and preventing the occurrence of bronchoconstriction.
Toxicology: Preclinical safety data: Acute Toxicity: LD50 (rats, by intratracheal): the highest possible dose (6.2 mg/kg of BDP + 12.4 mg/kg of S).
The association does not present toxicity; LD50 (rat, by IV): 51.3 mg/kg of BDP + 102.7 mg/kg of S; LD50 (rat, oral): 1407 mg/kg of BDP + 2814 mg/kg of S.
Chronic Toxicity: The administration of the association by inhalation in rats (n = 26) and dogs (n = 26) was well tolerated up to doses far above the expected in therapy.
The administration of the aerosol for 14 days in dogs did not show any sign of local intolerance.
Fetal toxicity and study of the effects on fertility: Studies in rats and rabbits have shown that the combination of drug Salbutamol and Beclometasone Pressurized Inhalation (100+50 micrograms/actuation) CFC FREE inhaler causes no adverse effect on breeding activity.
Mutagenesis: The product is not mutagenic.
Preclinical data on the propellant HFA-134a reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, reproductive toxicity and carcinogenic potential.
Salbutamol + Beclometasone dipropionate (Ibicar S) is intended for the treatment of bronchial asthma and COPD (chronic obstructive pulmonary disease), with asthmatic component.
Salbutamol + Beclometasone dipropionate (Ibicar S) is for Inhalation use only.
Children (above 6 years old): It is recommended to use one to two puffs every 12 hours (2 times daily), or every 8 hours (three times daily), or every 6 hours (4 times daily). Treatment in children should be done under adult supervision.
The maximum recommended daily dose is 8 puffs per day.
Adults: adults are recommended two puffs every 6 hours (4 times daily) or every 4 hours (6 times daily).
The maximum daily recommended dose is 12 puffs a day.
If patient takes two puffs at once do not use again before 4 hours.
Regarding duration of treatment, Salbutamol + Beclometasone dipropionate (Ibicar S) should be used only during the initial period of treatment and it is not recommended for continuous use in excess of ten days.
At high doses, some patients may experience transient side effects (slight increase in heart rate, mild muscle tremors) that disappear after the first day of treatment, reducing the dose if needed.
If a patient uses a quantity greater than that indicated for this medication, tachycardia, muscle tremors, restlessness, nausea, etc. may occur.
In this case, besides the monitoring of clinical signs and symptoms of the patient, the use of a cardioselective beta-blocker may be necessary.
Salbutamol + Beclometasone dipropionate (Ibicar S) inhaler is contraindicated in patients sensitive to any of the active substances or other components of the formulation.
Use of the product should be avoided in patients with pulmonary tuberculosis or viral infections.
This drug is contraindicated for children less than 6 years of age.
Salbutamol + Beclometasone dipropionate (Ibicar S) should be used only during the initial period of treatment and it is not recommended for continuous use in excess of ten days.
The use, especially for prolonged periods may lead to sensitization phenomena and, exceptionally to systemic side effects. In either case, it is necessary to discontinue treatment and to establish appropriate therapy.
The use of inhaled corticosteroids should not exceed the recommended doses: in case of persistent bronchospasm, it is appropriate to use beta2-agonist as needed.
The conduct of the treatment in patients already using corticosteroids requires special care and the doctor should follow up treatment.
After high doses of Salbutamol + Beclometasone dipropionate (Ibicar S) for prolonged periods, some degree of adrenal atrophy can be observed.
It is important that the dose of inhaled corticosteroids is determined in order to fit a minimum effective dose for asthma control, and this is reviewed regularly.
Possible systemic effects such as adrenal suppression, including growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma may occur after treatment with inhaled corticosteroids in high doses for long periods.
There have been rare cases of acute adrenal crisis in children exposed to higher doses of beclometasone than recommended (about 1000 mcg/day) for extended periods (several months or years). The first symptoms of adrenal insufficiency are nonspecific and include anorexia, abdominal pain, weight loss, fatigue, headaches, nausea, vomiting. In turn, the specific symptoms, in case of treatment with inhaled corticosteroids, include hypoglycemia, with decreased level of consciousness and/or convulsions.
Situations that could result in adrenal crisis are trauma, surgery, infection, and rapid reduction in dosage.
Patients receiving high doses of steroids should be carefully evaluated and have their dose gradually reduced. Monitoring of adrenal function may also be needed.
Sympathomimetics should be used with caution in patients who may be particularly sensitive to their effects.
In patients with coronary heart disease, arrhythmia, hypertension, glaucoma, hyperthyroidism, pheochromocytoma, diabetes, and prostatic hypertrophy, the product should be used only when absolutely necessary.
There is evidence in the literature of rare cases of myocardial ischemia associated with the use of salbutamol. Patients with existing heart problems (eg, ischemic heart disease, tachyarrhythmias or severe heart failure), receiving salbutamol for treatment of respiratory diseases should be advised to notify the physician in cases of chest pain or worsening symptoms of heart disease.
Patients should be warned that this product contains a small amount of ethanol (about 2.52 mg per puff), but the normal dosage, the amount of ethanol is negligible and does not constitute a risk to the patient.
Prolonged use may result in oropharyngeal candidiasis, which can usually be treated with alkalizing or local antimycotics, without interruption of treatment.
Pregnancy: Salbutamol + Beclometasone dipropionate (Ibicar S) is not recommended for use in the first three months of pregnancy. The decision of administration to the patient should be weighed against the risk/benefit.
Animal studies have not demonstrated fetal risk, but there are no controlled studies in pregnant women.
Lactation: Not recommended for use during lactation.
There is no experience or data on the safety of propellant HFA-134a in pregnancy or lactation in humans. However, studies on the effects of HFA-134a on reproductive function and embryonic development in animals have shown no clinically significant adverse effects.
Therefore, it is unlikely that adverse effects occur in humans.
This medicine should not be used by pregnant women without advice from their physician.
There were no reported serious side effects related to the use of Salbutamol + Beclometasone dipropionate (Ibicar S) at the recommended dose, only a few patients complained of hoarseness or dysphonia.
Candidiasis in the mouth or throat may occasionally occur. The incidence increases with doses greater than 400 mcg per day of product. This can be reduced or prevented by rinsing the mouth with water after each dose. This infection should be treated with topical antifungal medication and it is not necessary to interrupt the treatment.
At high doses, some patients may experience transient side effects (slight increase in heart rate, mild muscle tremors), which disappear after the first day of treatment, reducing the dose if needed.
Systemic side effects are extremely unlikely. However, their occurrence is related to extended use. Special care should be taken when using the drug for prolonged periods; the patient should be monitored to establish any systemic side effects (osteoporosis, peptic ulcer, signs of secondary adrenal insufficiency).
At high doses, used for long periods can occur adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.
Very rarely cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) and myocardial ischemia has been reported.
Very common reaction (> 1/10): Candidiasis in the mouth and throat.
Common reaction (> 1/100 and <1/10): paradoxical bronchospasm.
Unusual reaction (> 1/1,000 and <1/100): slight increase in heart rate, mild muscle tremors.
Rare reaction (> 1/10,000 and <1,000): adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma.
Very rare reaction (1/10,000): systemic side effects (osteoporosis, peptic ulcer, signs of secondary adrenal insufficiency) and arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles), myocardial ischemia.
There is a theoretical potential for interaction in particularly sensitive patients using disulfiram or metronidazole because Salbutamol + Beclometasone dipropionate (Ibicar S) inhaler contains ethanol and its interaction with disulfiram can result in redness and with metronidazole redness, vomiting and tachycardia can occur.
Salbutamol + Beclometasone dipropionate (Ibicar S) inhaler will interact with beta blockers (eg propranolol).
Patients should be advised that the drug contains a small percentage of alcohol. In normal doses, there is no risk to patients.
There are no known interactions with alcohol and nicotine to date. There were no changes to date in laboratory tests, possibly because it is a drug of local action with little systemic absorption.
Store at temperatures not exceeding 30°C. Do not freeze.
INSTRUCTIONS FOR PATIENT FOR USING THE INHALER WITHOUT SPACER: Important: Follow instructions carefully.
Shake the inhaler well immediately before each use.
1. Testing your inhaler: If you are using the inhaler for the first time or if the inhaler has not been used for a minimum of seven days, "test spray" the inhaler. Remove the cap from the mouthpiece; the mouthpiece should be inspected for the presence of foreign objects before each use. Spray the inhaler 2 times into the air after shaking the device prior to each actuation.
2. Make sure the canister is fully and firmly inserted into the actuator.
3. Hold the inhaler upright with your thumb on the base. Place either one or two fingers on the top of the canister. Breathe out fully through your mouth expelling as much air from your lungs as possible. Thereafter, place the mouthpiece of the inhaler in your mouth between your teeth.
4. Close your lips around it (do not bite it) tilt your head slightly backwards. Start breathing in slowly through your mouth. As you breathe in steadily and deeply, press down the canister to release one puff.
5. While holding their breath, patients should take out the inhaler from their mouth and should continue holding their breath for 10 seconds or for as long as it is comfortable. Breathe out slowly.
6. Note: If the second puff is required wait for at least one minute and repeat steps 2 through 5 for each puff prescribed by your Physician. Rinse your mouth or gargle with water after inhaling your recommended dose. This is likely to reduce the soreness that may be caused by the drug. After use, replace the mouthpiece cover.
7. Practice in front of the mirror for the first few times. If you see 'mist' coming from top of the inhaler or sides of the mouth, this indicates failure of technique. Start again from Step 2.
8. For Children: Children should use the inhaler under adult supervision, as instructed by the Physician.
Cleaning: Clean the inhaler at least once in a week.
1. Gently pull the metal canister out of the plastic body of the inhaler. Remove the mouthpiece cover.
2. Rinse the plastic body and the mouthpiece cover in warm/running water.
3. Dry thoroughly. Avoid excess heat.
4. Replace the canister and the mouthpiece cover correctly.
Discard the inhaler along with the canister after using the labeled number of inhalations.
DO NOT PUT THE METAL CONTAINER IN WATER.
R03AK13 - salbutamol and beclometasone ; Belongs to the class of adrenergics in combination with corticosteroids or other drugs, excluding anticholinergics. Used in the treatment of obstructive airway diseases.
Susp for inhalation 200 actuations x 1's.