Flutiform 250mcg/10mcg

Indications

• Chronic asthma
• Chronic obstructive pulmonary disease (COPD)
• Reversible airways obstruction
• Prophylaxis of exercise-induced bronchospasm

Dosage

Children: Child 6–11 years: 12 micrograms twice daily (maximum daily dose 24 micrograms). Child 12–17 years: 12 micrograms twice daily, may

Adults: 6–12 micrograms by inhalation 1–2 times a day, increased if necessary up to 24 micrograms twice daily (max. per dose 36 micrograms), with a maximum daily dose of 48 micrograms.

Mechanism of action

Formoterol fumarate acts as an agonist at beta-2 adrenergic receptors located on bronchial smooth muscle. Upon binding, it activates adenylate cyclase, increasing intracellular cyclic AMP (cAMP) levels, leading to relaxation of bronchial smooth muscle and bronchodilation. This mechanism results in improved airflow and reduced resistance in the airways.

Pharmacodynamics

The pharmacodynamic effect of formoterol fumarate includes bronchodilation and relief of bronchospasm associated with asthma and COPD. The duration of action is approximately 12 hours, allowing for twice-daily dosing in many cases. Formoterol also exhibits some anti-inflammatory effects, although its primary role is as a bronchodilator.

Pharmacokinetics

Formoterol fumarate is well-absorbed following inhalation, with peak plasma concentrations typically occurring within 15 to 30 minutes. It undergoes extensive metabolism in the liver, primarily via the cytochrome P450 system. The elimination half-life is approximately 10 hours. Renal impairment may necessitate dose adjustments, especially in severe cases, while hepatic impairment is advised against due to the risk of unpredictable conversion to terbutaline.

Contra-indications

• Hypersensitivity to formoterol or any component of the formulation
• Severe impairment or cirrhosis of liver
• Rapidly deteriorating asthma

Adverse effects

• Anxiety
• Abnormal behaviour
• Muscle cramps
• Sleep disorders
• Akathisia
• Angioedema
• Bronchospasm
• Circulatory collapse
• Dizziness
• Hypokalaemia
• Hypotension
• Myocardial ischaemia
• Nausea
• Skin reactions

Interactions

• Concomitant use with theophylline and its derivatives may potentiate hypokalaemia
• Corticosteroids may also increase the risk of hypokalaemia
• Diuretics can lead to additive effects on serum potassium levels

Precautions

• Caution in patients with a history of cardiovascular disease
• Monitor potassium levels in patients on high doses
• Use with caution in patients with severe asthma or those requiring high doses of beta-agonists

Pregnancy

Manufacturer advises to avoid use due to lack of information on safety during pregnancy.

Breast-feeding

Manufacturer advises to avoid use due to lack of information on safety during breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Inhalation powder (various dosage forms including 6 micrograms, 12 micrograms, and 24 micrograms per dose)

Indications

• Asthma maintenance therapy
• Chronic obstructive pulmonary disease (COPD)
• Allergic rhinitis
• Nasal polyps

Dosage

Adults: For asthma: 160 micrograms once daily, may be reduced to 80 micrograms once daily if control is maintained; may be increased to 320 micrograms twice daily if necessary. For allergic rhinitis:

Mechanism of action

Fluticasone propionate acts as a highly selective agonist at the human glucocorticoid receptor, exhibiting negligible activity at androgen, estrogen, or mineralocorticoid receptors. It activates glucocorticoid receptors and inhibits nuclear factor kappa B, which plays a crucial role in the inflammatory response. Additionally, fluticasone reduces the number of inflammatory mediator cells in the nasal mucosa and decreases nasal reactivity to allergens, leading to reduced release of inflammatory mediators and proteolytic enzymes.

Pharmacodynamics

Fluticasone's therapeutic effects are primarily local, resulting from the deposition of the inhaled drug on the nasal mucosa or lungs, rather than systemic effects from swallowed portions. Its anti-inflammatory action includes the inhibition of eosinophilia and other inflammatory cell types, contributing to the management of allergic conditions and symptoms of asthma. The drug is associated with vasoconstriction in the skin when used topically.

Pharmacokinetics

Fluticasone is administered via inhalation or intranasal routes, leading to low systemic absorption. Following inhalation, it is rapidly absorbed, with peak plasma concentrations occurring within one to two hours. The drug has a high protein binding rate and is extensively metabolized by the liver, primarily through cytochrome P450 enzymes. The elimination half-life is approximately 3 to 4 hours, with metabolites excreted primarily in feces and urine. Due to its significant first-pass metabolism, systemic exposure is minimized.

Contra-indications

• Hypersensitivity to fluticasone or any excipients
• Severe systemic fungal infections
• Untreated localized infections

Adverse effects

• Oral candidiasis
• Dysphonia
• Cough
• Nasal irritation
• Headache
• Throat irritation
• Nasal bleeding
• Increased risk of pneumonia in COPD patients

Interactions

• Cenobamate: Moderate interaction (decreases exposure)
• Cobicistat: Unknown interaction (increases exposure)
• Idelalisib: Unknown interaction (increases exposure)
• Mitotane: Unknown interaction (decreases exposure)
• Clarithromycin: Unknown interaction (increases exposure)
• Rifampicin: Unknown interaction (decreases exposure)

Precautions

• Caution in patients with tuberculosis, untreated systemic infections, or those with a history of severe allergies
• Monitor for signs of adrenal suppression in long-term use
• Use with caution in patients with hepatic impairment

Pregnancy

Fluticasone should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. Consultation with a healthcare provider is recommended.

Breast-feeding

Fluticasone is excreted in breast milk. Caution is advised when administered to breastfeeding women.

Storage

Store at room temperature, away from direct sunlight and moisture. Keep out of reach of children.

Formulations

• Pressurized inhalation aerosol: 320 micrograms/9 micrograms per dose
• Nasal spray: 50 micrograms per actuation
• Dry powder inhaler: 200 micrograms per dose

Indications

• Asthma
• Chronic obstructive pulmonary disease (COPD)

Dosage

Children: Refer to BNF for Children for specific dosing recommendations based on age and weight.

Adults: Refer to BNF for specific dosing guidance, typically involving the use of metered-dose inhalers or nebulizers.

Mechanism of action

Formoterol selectively binds to and activates beta2-adrenergic receptors, predominantly located in bronchial smooth muscle. This activation stimulates adenylyl cyclase, leading to increased levels of cyclic AMP (cAMP). Elevated cAMP causes relaxation of bronchial smooth muscle and dilation of the airways. Additionally, formoterol inhibits the release of hypersensitivity mediators, such as histamine and leukotrienes, from mast cells, further contributing to its bronchodilator effect.

Pharmacodynamics

As a bronchodilator, formoterol works locally in the lungs to relax smooth muscle and open the airways. It provides both a rapid onset of action and a prolonged duration, making it suitable for the management of chronic respiratory conditions. However, it should not be used as monotherapy in asthma management due to an associated increased risk of asthma-related death when not combined with inhaled corticosteroids.

Pharmacokinetics

Formoterol is administered via inhalation, allowing for direct delivery to the lungs. It has a rapid onset of action, typically within 2-3 minutes, and is characterized by a long duration of action, up to 12 hours. The pharmacokinetics of formoterol may vary based on individual patient factors, including age, lung function, and concurrent medications.

Contra-indications

• Hypersensitivity to formoterol or any of its components
• Severe uncontrolled asthma
• Acute bronchospasm
• Cardiovascular disorders
• Use of monoamine oxidase inhibitors (MAOIs) within 14 days

Adverse effects

• Tachycardia
• Palpitations
• Tremor
• Headache
• Nervousness
• Dizziness
• Nausea
• Muscle cramps
• Hypokalemia
• Hyperglycemia

Interactions

• Other sympathomimetics
• Beta-blockers (may reduce effectiveness of formoterol)
• Diuretics (may increase the risk of hypokalemia)
• Monoamine oxidase inhibitors (MAOIs)
• Tricyclic antidepressants

Precautions

• Caution in patients with cardiovascular disorders
• Caution in patients with diabetes mellitus
• Use with caution in patients with hyperthyroidism
• Monitor for worsening of asthma symptoms
• Avoid use as a rescue medication

Pregnancy

Formoterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult a healthcare provider.

Breast-feeding

It is not known whether formoterol is excreted in human milk. Caution should be exercised when prescribing to nursing women.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Aerosol inhaler
• Dry powder inhaler
• Nebuliser solution

Mechanism of action

[DB08906] and [DB00588] work through an unknown mechanism to affect the action of various cell types and mediators of inflammation. In vitro experiments show [DB08906] activating glucocorticoid receptors, inhibiting nuclear factor kappa b, and inhibiting lung eosinophilia in rats. [DB00588] performs similar activity but is not stated to affect nuclear factor kappa b. Fluticasone propionate is a highly selective agonist at the human glucocorticoid receptor with negligible activity at androgen, estrogen, or mineralocorticoid receptors. In preclinical studies, fluticasone propionate reportedly exhibited weak progesterone-like activity. However, as plasma concentrations of fluticasone propionate are very low following intranasal administration of the drug in recommended doses, the clinical importance of this finding is not known. The therapeutic effects of fluticasone propionate are thought to result from local actions of the deposited inhaled dose on the nasal mucosa rather than from the systemic actions of the swallowed portion of the dose. The exact mechanism(s) of anti-inflammatory action of corticosteroids in allergic rhinitis remains unknown, but may involve reductions in the following: number of mediator cells (basophils, eosinophils, helper-inducer [CD4+, T4] T-cells, mast cells, and neutrophils) in the nasal mucosa, nasal reactivity to allergens, and release of inflammatory mediators and proteolytic enzymes. Following exposure of patients with a history of allergic rhinitis to allergen, eosinophils, basophils, mast cells, T cells, and neutrophils appear to infiltrate nasal secretions and mucosa, releasing inflammatory mediators that generate allergic responses such as pruritus, sneezing, rhinorrhea, and nasal edema. /Corticosteroids/ Other mechanisms by which corticosteroids may improve symptoms of allergic rhinitis may involve inhibition of postcapillary venule dilation and permeability and facilitation of nasomucociliary clearance of nasal secretions. Patients receiving short- and long-term treatment with intranasal fluticasone propionate have demonstrated decreases in nasal turbinate swelling and mucosal inflammation. As inflammatory changes occur during periods of increased nasal hyperresponsiveness, the degree of response to nasal secretory stimuli has been used as an indirect measure of inflammation. In patients with asymptomatic seasonal allergic rhinitis, pretreatment with intranasal fluticasone propionate for 2-6 weeks prior to challenge with allergens or inflammatory mediatorsgenerally reduced the release of tryptase, histamine, eosinophilic cationic protein, and prostaglandin D2 in nasal biopsies or nasal lavage fluid; concentrations of eosinophils or activated eosinophils, CD4+ T-cells, and basophils also were reduced. /Corticosteroids/ Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

Pharmacodynamics

Systemically, in vitro experiments show [DB08906] activates glucocorticoid receptors, inhibits nuclear factor kappa b, and inhibits lung eosinophilia in rats. [DB00588] performs similar activity but is not stated to affect nuclear factor kappa b. [DB00588] as a topical formulation is also associated with vasoconstriction in the skin.

Mechanism of action

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. Formoterol is a long-acting selective stimulator of the beta2-adrenergic receptors in bronchial smooth muscle. This stimulation causes relaxation of smooth muscle fibers and produces bronchodilation. Formoterol stimulates beta2-adrenergic receptors and apparently has little or no effect on beta1- or alpha-adrenergic receptors. The drug's beta-adrenergic effects appear to result from stimulation of the production of cyclic adeno-3'-5'-monophosphate (cAMP)by activation of adenyl cyclase. Cyclic AMP mediate numerous cellular responses, increased concentrations of cAMP are associated with relaxation of bronchial smooth muscle and suppression of some aspects of inflammation, such as inhibition of release proinflammatory mast cell mediators(eg histamine, leukotrienes).

Pharmacodynamics

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.