Seretide Evohaler 25/250mg 120dz Gsk

UGX97,500.00

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Therapeutic indications

Seretide is indicated in the regular treatment of asthma where the 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.

4.2 Posology and method of administration

Posology

Route of administration: Inhalation use.

Patients should be made aware that Seretide Evohaler must be used daily for optimum benefit, even when asymptomatic.

Patients should be regularly reassessed by a doctor so that the strength of Seretide they are receiving remains optimal and is only changed on medical advice. The dose should be titrated to the lowest dose at which effective control of symptoms is maintained. Where the control of symptoms is maintained with the lowest strength of the combination given twice daily then the next step could include a test of inhaled corticosteroid alone. As an alternative, patients requiring a long-acting β2 agonist could be titrated to Seretide given once daily if, in the opinion of the prescriber, it would be adequate to maintain disease control. In the event of once-daily dosing when the patient has a history of nocturnal symptoms the dose should be given at night and when the patient has a history of mainly daytime symptoms the dose should be given in the morning.

Patients should be given the strength of Seretide containing the appropriate fluticasone propionate dosage for the severity of their disease. Note: Seretide 25 microgram/50 microgram strength is not appropriate for adults and children with severe asthma. If an individual patient should require dosages outside the recommended regimen, appropriate doses of β2 agonist and/or corticosteroid should be prescribed.

Recommended Doses:

Adults and adolescents 12 years and older:

– Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily.

or

– Two inhalations of 25 micrograms salmeterol and 125 micrograms fluticasone propionate twice daily.

or

– Two inhalations of 25 micrograms salmeterol and 250 micrograms fluticasone propionate twice daily.

A short-term trial of Seretide may be considered as initial maintenance therapy in adults or adolescents with moderate persistent asthma (defined as patients with daily symptoms, daily rescue use and moderate to severe airflow limitation) for whom rapid control of asthma is essential. In these cases, the recommended initial dose is two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily. Once control of asthma is attained treatment should be reviewed and consideration given as to whether patients should be stepped down to an inhaled corticosteroid alone. Regular review of patients as treatment is stepped down is important.

A clear benefit has not been shown as compared to inhaled fluticasone propionate alone used as initial maintenance therapy when one or two of the criteria of severity are missing. In general inhaled corticosteroids remain the first-line treatment for most patients. Seretide is not intended for the initial management of mild asthma. Seretide 25 micrograms/50 micrograms strength is not appropriate in adults and children with severe asthma; it is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed-combination can be used in patients with severe asthma.

Paediatric population

Children 4 years and older:

– Two inhalations of 25 micrograms salmeterol and 50 micrograms fluticasone propionate twice daily.

The maximum licensed dose of fluticasone propionate delivered by Seretide inhaler in children is 100 microgram twice daily.

The safety and efficacy of Seretide inhaler in children aged under 4 years have not been established (see Section 5.1).

Children <12 years old may have difficulties synchronising aerosol actuation with the inspiration of breath. Use of a spacer device with Seretide inhaler is recommended in patients who have or are likely to have difficulties to coordinate actuation with inspiration. A recent clinical study has shown that paediatric patients using a spacer achieved exposure similar to adults not using a spacer and paediatric patients using Diskus, confirming that spacers compensate for poor inhaler technique (see section 5.2).

Either the Volumatic or AeroChamber Plus spacer device can be used (depending on National Guidance). Limited data are available that demonstrate an increase in systemic exposure when the AeroChamber Plus spacer device is used compared with the Volumatic spacer device (see section 4.4).

Patients should be instructed in the proper use and care of their inhaler and spacer and their technique checked to ensure optimum delivery of the inhaled drug to the lungs. Patients should continue to use the same make of spacer device as switching between spacer devices can result in changes in the dose delivered to the lungs (see section 4.4).

Re-titration to the lowest effective dose should always follow the introduction or change of a spacer device.

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 the use of Seretide in patients with hepatic impairment.

Instructions for Use:

Patients should be instructed in the proper use of their inhaler (see patient information leaflet)

During inhalation, the patient should preferably sit or stand. The inhaler has been designed for use in a vertical position.

Testing the inhaler:

Before using for the first time patients should remove the mouthpiece cover by gently squeezing the sides of the cover, shake the inhaler well, hold the inhaler between the fingers and thumb with their thumb on the base, below the mouthpiece and release puffs into the air until the counter reads 120 to make sure that it works. The inhaler should be shaken immediately before releasing each puff. If the inhaler has not been used for a week or more the mouthpiece cover should be removed, the patient should shake the inhaler well and should release two puffs into the air. Each time the inhaler is activated the number on the counter will count down by one.

Use of the inhaler:

1. Patients should remove the mouthpiece cover by gently squeezing the sides of the cover.

2. Patients should check inside and outside of the inhaler including the mouthpiece for the presence of loose objects

3. Patients should shake the inhaler well to ensure that any loose objects are removed and that the contents of the inhaler are evenly mixed.

4. Patients should hold the inhaler upright between fingers and thumb with their thumb on the base, below the mouthpiece.

5. Patients should breathe out as far as is comfortable and then place the mouthpiece in their mouth between their teeth and close their lips around it. Patients should be instructed not to bite the mouthpiece.

6. Just after starting to breathe in through their mouth, patients should press firmly down on the top of the inhaler to release Seretide, while still breathing in steadily and deeply.

7. While holding their breath, patients should take the inhaler from their mouth and take their finger from the top of the inhaler. Patients should continue holding their breath for as long as is comfortable.

8. To take a second inhalation, patients should keep the inhaler upright and wait about half a minute before repeating steps 3 to 7.

9. Patients should immediately replace the mouthpiece cover in the correct orientation by firmly pushing and snapping the cap into position. This does not require excessive force, the cover should click into position.

IMPORTANT

Patients should not rush stages 5, 6 and 7. It is important that patients start to breathe in as slowly as possible just before operating their inhaler. Patients should practise in front of a mirror for the first few times. If they see “mist” coming from the top of their inhaler or the sides of their mouth they should start again from stage 3.

Patients should rinse their mouth out with water and spit out, and/or brush their teeth after each dose of medicine, in order to minimise the risk of oropharyngeal candidiasis and hoarseness

Patients should consider getting a replacement when the counter shows the number 020. The counter will stop at 000 when all the recommended puffs have been used. Replace the inhaler when the counter reads 000.

Patients should never try to alter the numbers on the counter or detach the counter from the metal canister. The counter cannot be reset and is permanently attached to the canister.

Cleaning (also detailed in patient information leaflet):

Your inhaler should be cleaned at least once a week.

1. Remove the mouthpiece cover.

2. Do not remove the canister from the plastic casing.

3. Wipe the inside and outside of the mouthpiece and the plastic casing with a dry cloth or tissue.

4. Replace the mouthpiece cover in the correct orientation. This does not require excessive force, the cover should click into position.

DO NOT PUT THE METAL CANISTER IN WATER

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Seretide Evohaler should not be used to treat acute asthma symptoms for which a fast and short-acting bronchodilator is required. Patients should be advised to have their inhaler to be used for relief in an acute asthma attack available at all times.

Patients should not be initiated on Seretide during an exacerbation, or if they have significantly worsening or acutely deteriorating asthma.

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

Increased requirements for use of reliever medication (short-acting bronchodilators) or decreased response to reliever medication indicate deterioration of asthma control and patients should be reviewed by a physician.

Sudden and progressive deterioration in control of asthma is potentially life-threatening and the patient should undergo an urgent medical assessment. Consideration should be given to increasing corticosteroid therapy.

Once asthma symptoms are controlled, consideration may be given to gradually reducing the dose of Seretide. Regular review of patients as treatment is stepped down is important. The lowest effective dose of Seretide should be used (see section 4.2).

Treatment with Seretide should not be stopped abruptly due to the risk of exacerbation. Therapy should be down titrated under physician supervision.

As with all inhaled medication containing corticosteroids, Seretide should be administered with caution in patients with active or quiescent pulmonary tuberculosis and fungal, viral or other infections of the airway. Appropriate treatment should be promptly instituted if indicated.

Rarely, Seretide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Seretide should be used with caution in patients with severe cardiovascular disorders or heart rhythm abnormalities and in patients with diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemia or patients predisposed to low levels of serum potassium.

There have been very rare reports of increases in blood glucose levels (see section 4.8) and this should be considered when prescribing to patients with a history of diabetes mellitus.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Seretide Evohaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

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 corticosteroids. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children) (see Paediatric population sub-heading below for information on the systemic effects of inhaled corticosteroids in children and adolescents). It is important, therefore, that the patient is reviewed regularly and the dose of inhaled corticosteroid is reduced to the lowest dose at which effective control of asthma is maintained.

Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000 micrograms. Situations, which could potentially trigger an acute adrenal crisis, include trauma, surgery, infection or any rapid reduction in dosage. Presenting symptoms are typically vague and may include anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreased level of consciousness, hypoglycaemia, and seizures. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Systemic absorption of salmeterol and fluticasone propionate is largely through the lungs. As the use of a spacer device with a metered-dose inhaler may increase drug delivery to the lungs it should be noted that this could potentially lead to an increase in the risk of systemic adverse effects. Single-dose pharmacokinetic data have demonstrated that the systemic exposure to salmeterol and fluticasone propionate may be increased as much as two-fold when the AeroChamber Plus spacer device is used with Seretide inhaler as compared with the Volumatic spacer device.

The benefits of inhaled fluticasone propionate therapy should minimise the need for oral steroids, but patients transferring from oral steroids may remain at risk of the impaired adrenal reserve for a considerable time. Therefore these patients should be treated with special care and adrenocortical function regularly monitored. Patients who have required high dose emergency corticosteroid therapy in the past may also be at risk. This possibility of residual impairment should always be borne in mind in emergency and elective situations likely to produce stress, and appropriate corticosteroid treatment must be considered. The extent of the adrenal impairment may require specialist advice before elective procedures.

Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see section 4.5).

There was an increased reporting of lower respiratory tract infections (particularly pneumonia and bronchitis) in a 3-year study in patients with Chronic Obstructive Pulmonary Disease (COPD) receiving salmeterol and fluticasone propionate as a fixed-dose combination administered via the Diskus/Accuhaler compared with placebo (see section 4.8). In a 3-year COPD study, older patients, patients with a lower body mass index (<25kg/m2) and patients with very severe disease (FEV1<30% predicted) were at greatest risk of developing pneumonia regardless of treatment. Physicians should remain vigilant for the possible development of pneumonia and other lower respiratory tract infections in patients with COPD as the clinical features of such infections and exacerbation frequently overlapIf a patient with severe COPD has experienced pneumonia the treatment with Seretide should be re-evaluated. The safety and efficacy of Seretide Evohaler have not been established in patients with COPD and therefore Seretide Evohaler is not indicated for use in the treatment of patients with COPD.

Concomitant use of systemic ketoconazole significantly increases systemic exposure to salmeterol. This may lead to an increase in the incidence of systemic effects (e.g. prolongation in the QTc interval and palpitations). Concomitant treatment with ketoconazole or other potent CYP3A4 inhibitors should, therefore, be avoided unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment (see section 4.5).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes, which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric Population

Children and adolescents <16years taking high doses of fluticasone propionate (typically ≥ 1000 micrograms/day) may be at particular risk. Systemic effects may occur, particularly at high doses prescribed for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid featuresadrenal suppression, acute adrenal crisis and growth retardation in children and adolescents and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression. Consideration should be given to referring the child or adolescent to a paediatric respiratory specialist.

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored. The dose of inhaled corticosteroid should be reduced to the lowest dose at which effective control of asthma is maintained.

4.5 Interaction with other medicinal products and other forms of interaction

β adrenergic blockers may weaken or antagonise the effect of salmeterol. Both non-selective and selective β blockers should be avoided in patients with asthma unless there are compelling reasons for their use. Potentially serious hypokalaemia may result from β2 agonist therapy. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics.

Concomitant use of other β adrenergic containing drugs can have a potentially additive effect.

Fluticasone Propionate

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first-pass metabolism and high systemic clearance mediated by cytochrome CYP3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome CYP3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundredfolds, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing’s syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side effects.

In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole and cobicistat-containing products, and moderate CYP3A inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side effects. Combinations should be avoided unless the benefit outweighs the potential increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

Salmeterol

Potent CYP3A4 inhibitors

Co-administration of ketoconazole (400 mg orally once daily) and salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 7 days resulted in a significant increase in plasma salmeterol exposure (1.4-fold Cmax and 15-fold AUC). This may lead to an increase in the incidence of other systemic effects of salmeterol treatment (e.g. prolongation of QTc interval and palpitations) compared with salmeterol or ketoconazole treatment alone (see section 4.4).

Clinically significant effects were not seen on blood pressure, heart rate, blood glucose and blood potassium levels. Co-administration with ketoconazole did not increase the elimination half-life of salmeterol or increase salmeterol accumulation with repeat dosing.

The concomitant administration of ketoconazole should be avoided unless the benefits outweigh the potentially increased risk of systemic side effects of salmeterol treatment. There is likely to be a similar risk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir).

Moderate CYP 3A4 inhibitors

Co-administration of erythromycin (500 mg orally three times a day) and salmeterol (50 micrograms inhaled twice daily) in 15 healthy subjects for 6 days resulted in a small but non-statistically significant increase in salmeterol exposure (1.4-fold Cmax and 1.2-fold AUC). Co-administration with erythromycin was not associated with any serious adverse effects.

4.6 Fertility, pregnancy and lactation

Fertility

There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility.

Pregnancy

A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicates no malformative or feto/neonatal toxicity related to Seretide. Animal studies have shown reproductive toxicity after administration of β2 adrenoreceptor agonists and glucocorticosteroids (see section 5.3).

Administration of Seretide to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.

The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.

Breastfeeding

It is unknown whether salmeterol and fluticasone propionate/metabolites are excreted in human milk.

Studies have shown that salmeterol and fluticasone propionate, and their metabolites, are excreted into the milk of lactating rats.

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Seretide therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

Seretide Evohaler has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

As Seretide 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/fluticasone propionate are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000) and not known (cannot be estimated from the available data). Frequencies were derived from clinical trial data. The incidence in the placebo was not taken into account.

System Organ Class Adverse Event Frequency
Infections & Infestations Candidiasis of the mouth and throat

Pneumonia

Bronchitis

Oesophageal candidiasis

Common

Common1,3

Common1,3

Rare

Immune System Disorders Hypersensitivity reactions with the following manifestations:

Cutaneous hypersensitivity reactions

Angioedema (mainly facial and oropharyngeal oedema)

Respiratory symptoms (dyspnoea)

Respiratory symptoms (bronchospasm)

Anaphylactic reactions including anaphylactic shock

 

Uncommon

Rare

Uncommon

Rare

Rare

Endocrine Disorders Cushing’s syndrome, Cushingoid features, Adrenal suppression, Growth retardation in children and adolescents, Decreased bone mineral density Rare4
Metabolism & Nutrition Disorders Hypokalaemia

Hyperglycaemia

Common3

Uncommon4

Psychiatric Disorders Anxiety

Sleep disorders

Behavioural changes, including psychomotor hyperactivity and irritability (predominantly in children)

Depression, aggression (predominantly in children)

Uncommon

Uncommon

Rare
Not Known

Nervous System Disorders Headache

Tremor

Very Common1

Uncommon

Eye disorder Cataract

Glaucoma

Vision, blurred

Uncommon

Rare4

Not known4

Cardiac Disorders Palpitations

Tachycardia

Cardiac arrhythmias (including supraventricular tachycardia and extrasystoles).

Atrial fibrillation

Angina pectoris

Uncommon

Uncommon

Rare
Uncommon

Uncommon

Respiratory, Thoracic & Mediastinal Disorders Nasopharyngitis

Throat irritation

Hoarseness/dysphonia

Sinusitis

Paradoxical bronchospasm

Very Common2,3

Common

Common

Common1,3

Rare4

Skin and subcutaneous tissue disorders Contusions Common1,3
Musculoskeletal & Connective Tissue Disorders Muscle cramps

Traumatic fractures

Arthralgia

Myalgia

Common

Common1,3

Common

Common

1. Reported commonly in the placebo

2. Reported very commonly in the placebo

3. Reported over 3 years in a COPD study

4. See section 4.4

Description of selected adverse reactions

The pharmacological side effects of β2 agonist treatment, such as tremor, palpitations and headache, have been reported, but tend to be transient and reduce with regular therapy.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting bronchodilator and should be treated straightaway. Seretide Evohaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat and, rarely, of the oesophagus can occur in some patients. Both hoarseness and incidence of mouth and throat candidiasis may be relieved by rinsing the mouth with water and/or brushing the teeth after using the product. Symptomatic mouth and throat candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Seretide Evohaler.

Paediatric population

Possible systemic effects include Cushing’s syndrome, Cushingoid featuresadrenal suppression and growth retardation in children and adolescents (see section 4.4). Children may also experience anxiety, sleep disorders and behavioural changes, including hyperactivity and irritability.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product are important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

There are no data available from clinical trials on overdose with Seretide, however, data on overdose with both drugs are given below:

The signs and symptoms of salmeterol overdose are dizziness, increases in systolic blood pressure, tremor, headache and tachycardia. If Seretide therapy has to be withdrawn due to overdose of the β agonist component of the drug, provision of appropriate replacement steroid therapy should be considered. Additionally, hypokalaemia can occur and therefore serum potassium levels should be monitored. Potassium replacement should be considered.

Acute: 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, as verified by plasma cortisol measurements.

Chronic overdose of inhaled fluticasone propionate: Adrenal reserve should be monitored and treated with a systemic corticosteroid may be necessary. When stabilised, treatment should be continued with an inhaled corticosteroid at the recommended dose. Refer to section 4.4: risk of adrenal suppression.

In cases of both acute and chronic fluticasone propionate overdose, Seretide therapy should be continued at a suitable dosage for symptom control.

 

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