Combisure

Combisure Uses, Dosage, Side Effects, Food Interaction and all others data.

Fluticasone propionate is a glucocorticoid with high topical anti-inflammatory potency, but a low HPA-axis suppressive activity after dermal administration. It, therefore, has a therapeutic index which is greater than most of the commonly available steroids. Fluticasone propionate has a high degree of selectivity for the glucocorticoid receptor. In vitro studies show that fluticasone propionate has a strong affinity for, and agonist activity at, human glucocorticoid receptors. This receptor is believed to be responsible for the anti-inflammatory properties of glucocorticoids.

Fluticasone propionate has weak affinity for the progesterone receptor, and virtually no affinity for the mineralocorticoid, estrogen, or androgen receptors. The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. The half-life of the Fluticasone propionate glucocorticoid-receptor complex is approximately 10 hours.

Systemically, in vitro experiments show Fluticasone furoate activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. Fluticasone propionate performs similar activity but is not stated to affect nuclear factor kappa b. Fluticasone propionate as a topical formulation is also associated with vasoconstriction in the skin.

Formoterol fumarate is a long-acting β2-adrenergic receptor agonist (β2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at β2-receptors than at β1-receptors. Although β2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and β1-receptors are the predominant receptors in the heart, there are also β2-receptors in the human heart comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective β2-agonists may have cardiac effects.

The pharmacologic effects of β2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) and a long duration of action (up to 12 hours). The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death.

Combisure
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Combisure
Generic	Formoterol + Fluticasone
Weight	6mcg
Type	Inhaler
Therapeutic Class
Manufacturer	Sun Pharma
Available Country	India
Last Updated:	September 19, 2023 at 7:00 am

Uses

Fluticasone Propionate is used for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive eczema or dermatitis.

Treatment of Asthma: Formoterol Fumarate is used for the treatment of asthma and in the prevention of bronchospasm only as concomitant therapy with a long-term asthma control medication, such as an inhaled corticosteroid, in adults and children 5 years of age and older with reversible obstructive airways disease, including patients with symptoms of nocturnal asthma.

Prevention of Exercise-Induced Bronchospasm: Formoterol Fumarate is also used for the acute prevention of exercise-induced bronchospasm in adults and children 5 years of age and older, when administered on an occasional, as-needed basis. Use of Formoterol Fumarate as a single agent for the prevention of exercise-induced bronchospasm may be clinically used for patients who do not have persistent asthma. In patients with persistent asthma, use of Formoterol Fumarate for the prevention of exercise-induced bronchospasm may be clinically used, but the treatment of asthma should include a long-term asthma control medication, such as an inhaled corticosteroid.

Maintenance Treatment of Chronic Obstructive Pulmonary Disease: Formoterol Fumarate is used for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with Chronic Obstructive Pulmonary Disease including chronic bronchitis and emphysema.

Combisure is also used to associated treatment for these conditions: Asthma, Bronchostenosis, Skin discomfort, Moderate, severe Chronic Obstructive Pulmonary Disease (COPD)Asthma, Bronchial Asthma, Bronchoconstriction, Chronic Obstructive Pulmonary Disease (COPD), Exercise-Induced Bronchospasm, Moderate to Severe COPD

How Combisure works

Fluticasone furoate and Fluticasone propionate work through an unknown mechanism to affect the action of various cell types and mediators of inflammation. In vitro experiments show Fluticasone furoate activating glucocorticoid receptors, inhibiting nuclear factor kappa b, and inhibiting lung eosinophilia in rats. Fluticasone propionate performs similar activity but is not stated to affect nuclear factor kappa b.

Formoterol is a relatively selective long-acting agonist of beta₂-adrenergic receptors, although it does carry some degree of activity at beta₁ and beta₃ receptors. Beta₂ receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta₁ receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta₂ receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta₂ receptors over beta₁ receptors.

On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells.

Dosage

Combisure dosage

Cream: Apply a thin layer of Fluticasone propionate cream to the affected skin areas once daily.

Ointment: Apply a thin layer of Fluticasone propionate Ointment to the affected skin areas twice daily.

Inhalation Acute bronchospasm; Reversible airways obstruction:

As inhalation cap: 12 mcg twice daily, up to 24 meg twice daily in severe cases.
As dry powder inhaler: 6 or 12 mcg 1 -2 times/day, up to to 24 mcg twice daily in sever cases. As metered doses from aerosol inhaler: 12 or 24 mcg twice daily.

Prevention of exercise-induced bronchospasm: 6 or 12 mcg at least 15 mins before exercise. Additional doses may be given 12 hr later.

Side Effects

The fluticasone propionate preparations are usually well tolerated; local burning and pruritus have been reported. If signs of hypersensitivity appear, application should be stopped immediately. Prolonged and intensive treatment with potent corticosteroid preparations may cause local atrophic changes in the skin such as thinning, striae, dilatation of the superficial blood vessels, hypertrichosis and hypopigmentation.

Secondary infection, particularly when occlusive dressings are used or when skin folds are involved and allergic contact dermatitis have also been reported with corticosteroid use. Exacerbation of the signs and symptoms of the dermatoses have been reported with corticosteroid use.

Prolonged use of large amounts of corticosteroids, or treatment of extensive areas, can result in sufficient systemic absorption to produce the features of hypercorticism. This effect is more likely to occur in infants and children, and if occlusive dressings are used. In infants, the napkin may act as an occlusive dressing.

Common side effects are Viral infection, Bronchitis, Chest infection, Dyspnea , Chest pain, Tremor, Dizziness, Angina, Arrhythmias, Hypo/hypertension, Tachycardia, Hypokalemia, Hyperglycemia, Metabolic acidosis, Headache, Insomnia, Paradoxical bronchospasm, Severe asthma exacerbation

Toxicity

Fluticasone furoate administered nasally may be associated with adrenal suppression or an increase in QTc interval though the association has not been well demonstrated in studies. Fluticasone furoate requires no dosage adjustment in renal impairment but must be used in caution in hepatic impairment due to the elimination mechanisms. Fluticasone furoate is not associated with carcinogenicity, mutagenicity, or impairment of fertility. There are no well controlled studies in pregnancy or lactation though animal studies have shown teratogenicity and hypoadrenalism in the offspring of treated mothers and other corticosteroids are known to be excreted in breast milk. Generally, there are no reported adverse effects with fluticasone in pregnancy. Pediatric patients should be given the lowest possible dose and monitored for reduction in growth velocity. There is insufficient evidence to determine whether geriatric patients respond differently to other patients. Systemic exposure may be 27-49% higher in Japanese, Korean, and Chinese patients compared to Caucasian patients. Caution should be exercised in these patients and the benefit and risk should be assessed before deciding on a treatment.

Fluticasone propionate's use in specific populations has not been well studied. Fluticasone propionate is not carcinogenic, mutagenic, or clastogenic, nor did it affect fertility in animal studies. Subcutaneous Fluticasone propionate has been shown to produce teratogenic effects in rats though oral administration does not. Generally, there are no reported adverse effects with fluticasone in pregnancy. Fluticasone propionate in human milk may cause growth suppression, effects on endogenous corticosteroid production, or other effects. Pediatric patients treated with Fluticasone propionate ointment experienced adrenal suppression. Geriatric patients treated with Fluticasone propionate did not show any difference in safety or efficacy compared to other patient groups, though older patients may be more sensitive to adverse effects. There is no difference in the clearance of Fluticasone propionate across genders or race. Patients with hepatic impairment should be closely monitored due to the elimination mechanism.

The oral LD₅₀ in rats is 3130 mg/kg.

Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc. Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis. Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring. Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate.

Precaution

Fluticasone propionate has a very low propensity for systemic absorption, nevertheless, prolonged application of high doses to large areas of body surface, especially in infants and small children might lead to adrenal suppression. Children may absorb proportionally larger amounts of topical corticosteroids and thus be more susceptible to systemic toxicity.

The face, more than other areas of the body, may exhibit atropic changes after prolonged treatment with potent topical corticosteroids. This must be borne in mind when treating severe eczema.

Appropriate antimicrobial therapy should be used whenever treating inflammatory lesions which have become infected. Any spread of infection requires withdrawal of topical corticosteroid therapy and systemic administration of antimicrobial agents. Bacterial infection is encouraged by the warm, moist conditions induced by occlusive dressing, and so the skin should be cleansed before a fresh dressing is applied.

Thyrotoxicosis; severe CV disorders e.g. ischaemic heart disease, tachyarrhythmias or severe heart burn; prolonged QT-interval. DM; pregnancy; lactation; children, do not initiate or increase the dose during an exacerbation. May produce paradoxical bronchospasm.

Interaction

Concomitant treatment with xanthine derivatives, steroids or diuretics may potentiate a possible hypokalaemic effect of beta-agonists. Increased susceptibility to cardiac arrhythmias in patients treated with digitalis. Concomitant use with quinidine, disopyramide, procainamide, phenothiazines, antihistamines, MAOI or TCAs can prolong the QT-interval and increase the risk of ventricular arrhythmias. L-dopa, L-thyroxine, oxytocin and alcohol can impair cardiac tolerance towards beta2-sympathomimetics. beta-adrenergic blockers can inhibit the effect of formoterol. Increased risk of arrhythmias in patients receiving concomitant anaesthesia with halogenated hydrocarbons.

Volume of Distribution

608L at steady state for intravenous administration of Fluticasone furoate. Other reports suggest the mean volume of distribution at steady state is 661L. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 704L following intravenous administration.

The volume of distribution of intravenous Fluticasone propionate is 4.2L/kg. A study of 24 healthy Caucasian males showed a volume of distribution at steady state of 577L following intravenous administration.

Elimination Route

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The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut).

Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol T_max ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, C_max and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, T_max ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, C_max and AUC_0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C_max and AUC_0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges.

Half Life

15.1 hours for intranasal Fluticasone furoate and 24 hours for the inhaled formulation. A study of 24 healthy Caucasian males showed a half life of 13.6 hours following intravenous administration and 17.3-23.9 hours followed inhalation.

7.8 hours for intravenous Fluticasone propionate. A study of 24 healthy Caucasian males shows a half life of 14.0 hours following intravenous administration and 10.8 hours following inhalation.

The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation.