Protide Inhaler 25mcg+125mcg

Product Information

PROTIDE HFA

Protide® HFA

Salmeterol (as SalmeterolXinafoate) & Fluticasone Propionate

Presentation

Protide 25/125 HFA: Each metered dose actuation delivers SalmeterolXinafoate BP equivalent to Salmeterol 25mcg and Fluticasone

Propionate BP 125mcg.

Protide 25/250 HFA: Each metered dose actuation delivers SalmeterolXinafoate BP equivalent to Salmeterol 25mcg and Fluticasone

Propionate BP 250mcg.

Indications

Protide is indicated in the regular treatment of asthma where use of a combination product (long-acting beta 2 agonist and inhaled

corticosteroid) is appropriate:

– patients not adequately controlled with inhaled corticosteroids and ‘as needed’ inhaled short- acting beta 2 agonist or patients

already adequately controlled on both inhaled corticosteroid and long-acting beta 2 agonist

Dosage & Administration

Posology

Route of administration: Inhalation use.

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

Patients should be regularly reassessed by a doctor, so that the strength of Protide HFA 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 beta 2 agonist

could be titrated to Protide 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 Protide containing the appropriate fluticasone propionate dosage for the severity of

their disease. Note: Protide 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 beta 2 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 Protide may be considered as initial maintenance therapy in adults or adolescents with moderate persistent

asthma 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. Protide is not intended for the initial management of mild asthma. Protide 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 Protide HFA inhaler in children is 100 microgram twice daily.

There are no data available for use of Protide inhaler in children aged under 4 years.

Children<12 years old may have difficulties synchronising aerosol actuation with inspiration of breath. Use of a spacer device

with Protide 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 paediatricpatients using a spacer achieved exposure similar to adults not

using spacer and paediatric patients using Diskus, confirming that spacers compensate for poor inhaler technique.

Spacer device can be used. 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. 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 use of Protide in patients with hepatic impairment.

Instructions for Use: Patients should be instructed in the proper use of their inhaler

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 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.

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 mouth piece.

6. Just after starting to breathe in through their mouth, patients should press firmly down on the top of the inhaler to release

Protide, 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 practice 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.

Cleaning:

Your inhaler should be cleaned at least once a week.

1. Remove the mouth piece 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

Contra-indications, warnings etc.

Hypersensitivity to the active substances or to any of the excipients.

Special warnings and precautions for use: Protide HFA 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 Protide HFA 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 Protide HFA. Patients should be asked to

continue treatment but to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation on Protide HFA.

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 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 Protide. Regular review of

patients as treatment is stepped down is important. The lowest effective dose of Protide should be used.

Treatment with Protide should not be stopped abruptly due to risk of exacerbation. Therapy should be down-titrated under physician

supervision.

As with all inhaled medication containing corticosteroids, Protide 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, Protide may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild

transient reduction in serum potassium at high therapeutic doses. Protide should be used with caution in patients with severe

cardiovascular disordersor 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 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.

The pharmacological side effects of beta 2 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). 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 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. 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 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.

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. In a 3-year COPD study, older patients, patients with a

lower body mass index (<25 kg/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

overlap. If a patient with severe COPD has experienced pneumonia the treatment with Protide should be re-evaluated. The safety and

efficacy of Protide 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.

Paediatric population: Children and adolescents <16 years taking high doses of fluticasone propionate (typically ³ 1000

micrograms/day) may be at particular risk of systemic effects. Systemic effects may occur, particularly at high doses prescribed

for long periods. Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression, acute adrenal

crisis and growth retardation in children and adolescents and more rarely, a range of psychological or behavioral 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.

Drug Interaction: Interaction with other medicinal products and other forms of interaction beta adrenergic blockers may weaken or

antagonise the effect of salmeterol. Both non-selective and selective beta blockers should be avoided in patients with asthma,

unless there are compelling reasons for their use. Potentially serious hypokalaemia may result from beta 2 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 beta 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 P450 3A4 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 P450 3A4

inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, 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 moderate CYP3A

inhibitors, such as erythromycin, is also expected to increase the systemic fluticasone propionate exposure and the risk of

systemic side effects. Caution is recommended and long-term treatment with such drugs should if possible be avoided.

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.

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.

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 moderate amount of data on pregnant women (between 300 to 1000 pregnancy outcomes) indicate no malformative or

feto/neonatal toxicity of salmeterol and fluticasone propionate. Animal studies have shown reproductive toxicity after

administration of beta 2 adrenoreceptor agonists and glucocorticosteroids.

Administration of Protide 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 Protide HFA therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the

woman.

Side effects: As Protide HFA 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.

Description of selected adverse reactions: The pharmacological side effects of beta 2 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. Protide HFA

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 Protide HFA.

Paediatric population: Possible systemic effects include Cushing’s syndrome, Cushingoid features, adrenal suppression and growth

retardation in children and adolescents. 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 is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Overdose: There are no data available from clinical trials on overdose with ProtideHFA, 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 Protide HFA therapy has to be withdrawn due to overdose of the beta 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 treatment with a systemic

corticosteroid may be necessary. When stabilised, treatment should be continued with an inhaled corticosteroid at the recommended

dose.

In cases of both acute and chronic fluticasone propionate overdose, Protide HFA therapy should be continued at a suitable dosage

for symptom control.

Pharmaceutical precautions

Store in a cool and dry place, protected from light.

Packaging quantities

Protide 25/125 HFA: Each canister contains 120 metered dose.

Protide 25/250 HFA: Each canister contains 120 metered dose.

Manufactured by

UniMed&UniHealth Manufacturers Ltd.

B K Bari, Gazipur, Bangladesh

® Registered Trademark