Bexitrol F Multidose Dry Powder Inhaler (MDPI)

Bexitrol F is indicated in the regular treatment of asthma where use of a combination product (long-acting β2-agonist and inhaled corticosteroid) is appropriate:

• patients not adequately controlled with inhaled corticosteroids and 'as needed' inhaled short acting β2-agonist or
• patients already adequately controlled on both inhaled corticosteroid and long-acting β2-agonist.

Salmeterol Xinafoate is a selective, long-acting beta-2 agonist used in the treatment of asthma and other forms of diffuse airway obstruction. Fluticasone Propionate is a corticosteroid with mainly glucocorticoid activity. Fluticasone Propionate is stated to exert a topical effect on the lungs without systematic effects at usual dose. Salmeterol protects against symptoms, Fluticasone Propionate improves lung function and prevents exacerbations of the condition. This preparation can offer a more convenient regime for patients on concurrent β-agonist and inhaled corticosteroid therapy. The respective mechanisms of action of both drugs are discussed below:

Salmeterol: Salmeterol is a selective long-acting (12-hour) beta-2-adrenoceptor agonist with a long side chain that binds to the exo-site of the receptor.

Fluticasone Propionate: Fluticasone Propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, resulting in reduced symptoms and exacerbations of asthma, without the adverse effects observed when corticosteroids are administered systemically.

Inhaler:

• Adults and adolescents 12 years and older: 2 puffs of 25 µg Salmeterol and 50 µg Fluticasone Propionate twice daily or 2 puffs of 25 µg Salmeterol and 125 µg Fluticasone Propionate twice daily or 2 puffs of 25 µg Salmeterol and 250 µg Fluticasone Propionate twice daily.
• Children (4-12 years): 2 puffs of 25 µg salmeterol and 50 µg Fluticasone Propionate twice daily.

Inhalation capsule (for asthma):

• Adult and Adolescent (12 Years and Older): Salmeterol 50 µg & Fluticasone 100 µg or Salmeterol 50 µg & Fluticasone 250 µg twice daily (morning and evening, approximately 12 hours apart). 
• The recommended starting dosages for Salmeterol 50 µg & Fluticasone 100 µg & Salmeterol 50 µg & Fluticasone 250 µg for patients aged 12 years and older are based upon patients asthma severity. 
• The maximum recommended dosage is Salmeterol 50 µg & Fluticasone 500 µg twice daily.
• Pediatric Patients (4 to 11 Years): For patients with asthma who are not controlled on an inhaled corticosteroid, the dosage is Salmeterol 50 µg & Fluticasone 100 µg twice daily (morning and evening, approximately 12 hours apart).

Inhalation capsule (For COPD): Salmeterol 50 µg & Fluticasone 250 µg twice daily (morning and evening, approximately 12 hours apart). Rinsing the mouth after each inhalation is advised.


Maxhaler (For Asthma): This is a moulded plastic device containing a foil strip with 60 regularly placed blisters containing pre-dispensed inhalation powder. Patients should be made aware that inhaler must be used daily for optimum benefit, even when asymptomatic.

Adults and Adolescents (12 years and older)-

• 50/100 inhaler: One Inhalation twice daily
• 50/250 inhaler: One Inhalation twice daily
• 50/500 inhaler: One Inhalation twice daily

Children (4 years and older)-

• 50/100 inhaler: One Inhalation twice daily. The maximum licensed dose of fluticasone propionate delivered by this inhaler in children is 100 mcg twice daily. There are no data available for use of this inhaler in children aged under 4 years.

Maxhaler (For COPD):

• Inhaler: One Inhalation twice daily
• Special patient groups: There is no need to adjust the dose in elderly patients or in those with renal impairment. There are no data available for use of this in patients with hepatic impairment.
• Using the inhaler: This is a patient friendly, ready to use and easy to grip device. Use as per instructions for use.

Using an Inhaler seems simple, but most patients do not know how to use it in the right way. If the Inhaler is used in the wrong way, less medicine can reach the lungs. Correct and regular use of the Inhaler will prevent or lessen the severity of asthma attacks.

Following simple steps can help to use Inhaler effectively (According to "National Asthma Guidelines for Medical Practitioners" published by Asthma Association):

1. Take off the cap.
2. Shake the inhaler (at least six times) vigorously before each use.
3. If the inhaler is new or if it has not been used for a week or more, shake it well and release one puff into the air to make sure that it works.
4. Breathe out as full as comfortably possible & hold the inhaler upright.
5. Place the actuator into mouth between the teeth and close lips around the mouthpiece.
6. While breathing deeply and slowly through the mouth, press down firmly add fully on the canister to release medicine.
7. Remove the inhaler from mouth. Continue holding breath for at least for 10 seconds or as long as it is comfortable.
8. If doctor has prescribed more than one inhalation per treatment, wait 1 minute between puffs (inhalations). Shake the inhaler well and repeat steps 4 to 7.
9. After use, replace the cap on the mouthpiece. After each treatment, rinse mouth with water.
10. Check your technique in front of a mirror from time to time, if you see a white mist during the inhalation, you may not have closed your lips properly around mouthpiece, or you may not be breathing in as you press the can. This indicates failure of technique. If this happens, repeat the procedure from step 4 carefully.

Instructions for Cleaning Inhaler: Clean your Inhaler at least once a week. Remove canister and rinse the plastic actuator and cap in warm water but do not put the metal canister into water. Dry the actuator and cap thoroughly and gently replace the metal canister into the actuator with a twisting motion. Put the cap on the mouthpiece.

Both non-selective and selective β-blockers should be avoided in patients with asthma, unless there are compelling reasons for their use. Due to the very low plasma concentrations achieved after inhaled dosing clinically significant drug interactions are unlikely. Care should be taken when co-administering known strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir), as there is potential for increased systemic exposure to Fluticasone Propionate.

This is contraindicated in patients with a history of hypersensitivity to salmeterol xinafoate, fluticasone propionate or any of the excipients. This is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

As Bexitrol F contains Salmeterol and Fluticasone Propionate, the type and severity of adverse reactions associated with each of the compounds may be expected. There is no incidence of additional adverse events following concurrent administration of the two compounds. Adverse events, which have been associated with Salmeterol or Fluticasone Propionate, are given below.

Salmeterol: The pharmacological side effects of beta-2-agonist treatment, such as tremor, subjective palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy. Cardiac arrhythmia (including atrial fibrillation, supraventricular tachycardia and extra systoles) may occur, usually in susceptible patients. There have been reports of arthralgia and hypersensitivity reactions, including rash, oedema and angioedema. There have been reports of oropharyngeal irritation. There have been rare reports of muscle cramps.

Fluticasone propionate: Hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Cutaneous hypersensitivity reactions have been reported. Rare cases of facial and oropharyngeal oedema have been reported. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after use of Salmeterol/ Fluticasone Propionate Inhaler.

Pregnancy: Administration of this inhalation capsule during pregnancy and lactation should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus or child. There is insufficient experience of the use of salmeterol xinafoate and fluticasone propionate in human pregnancy. Reproductive toxicity studies in animals, either with single agent or in combination, revealed the fetal effects expected at excessive systemic exposure levels of a potent beta-2- adrenoreceptor agonist & glucocorticosteroid.

Lactation: Administration of this inhalation capsule in breast-feeding mothers should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus or child. There is insufficient experience of the use of salmeterol xinafoate and fluticasone propionate in human lactation. Salmeterol and fluticasone propionate concentrations in plasma after inhaled therapeutic doses are very low and therefore concentrations in human breast milk are likely to be correspondingly low. This is supported by studies in lactating animals, in which low concentrations were measured in milk. There are no data available for human breast milk.

Use in asthma patients: This inhalation capsule should not be initiated in patients during an exacerbation, or if they have unstable or acutely deteriorating asthma. This inhalation capsule is not for relief of acute symptoms for which a fast and short-acting bronchodilator (e.g. salbutamol) is required. Patients should be advised to have their relief medication available at all times.

Asthma-related adverse events: Serious asthma-related adverse events and exacerbations may occur during treatment with this inhalation capsule. Patients should be asked to continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation of this inhalation capsule.

Paradoxical Bronchospasm: As with other inhalation therapy paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast and short-acting inhaled bronchodilator. This inhalation capsule should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary. The pharmacological side-effects of beta-2 agonist treatment, such as tremor, subjective palpitations and headache have been reported, but tend to be transient and to reduce with regular therapy.

Use in COPD patients: There was an increased reporting of pneumonia in studies of patients with COPD receiving salmeterol/fluticasone inhaler. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.

Corticosteroids: This inhalation capsule contains an inhaled corticosteroid (fluticasone propionate). Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods; these effects are much less likely to occur than with oral. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation and (very rarely) behavioral disturbances in children and adolescents, decrease in bone mineral density, cataract and glaucoma. Therefore, it is important, that the patient is reviewed regularly and the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control is maintained.

Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to paediatric patients. The long-term effects of this reduction including the impact of final adult height are unknown.

No human over dosage data has been reported for Bexitrol F inhaler; however data on overdose with both drugs are given below:

Salmeterol: The signs and symptoms of Salmeterol overdose are seizures, angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Other signs of overdosage may include hypokalemia and hyperglycemia. Treatment consists of discontinuation of Salmeterol together with appropriate cardioselective beta-blocking agents, which should be used with caution in patients with a history of bronchospasm.

Fluticasone Propionate: Acute inhalation of Fluticasone Propionate doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not need emergency action as adrenal function is recovered in a few days. Chronic overdose of inhaled Fluticasone Propionate may lead to adrenal suppression. Monitoring of adrenal reserve may be necessary. In cases of Fluticasone Propionate overdose Bexitrol F inhaler therapy may still be continued at a suitable dosage for symptom control.

Long-acting selective β-adrenoceptor stimulants, Respiratory corticosteroids

Pressurised canister, do not puncture, break or incinerate even when apparently empty. Avoid storage in direct sunlight or heat. Store below 30°C. Keep away from eyes. Keep away from children.