Asthma
Rolenium 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.
Chronic Obstructive Pulmonary Disease (COPD)
Rolenium is indicated for the symptomatic treatment of patients with COPD (FEV1 <50% predicted normal) and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy.

Rolenium is for inhalation use only.
Patients should be made aware that Rolenium must be used daily for optimum benefit, even when asymptomatic.
Patients should be regularly reassessed by a doctor, so that the dose of Rolenium 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 Rolenium 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 day-time symptoms the dose should be given in the morning.

Patients should be given the strength of Rolenium containing the appropriate fluticasone propionate dosage for the severity of their disease. Prescribers should be aware that, in patients with asthma, fluticasone propionate is as effective as other inhaled steroids at approximately half the microgram daily dose. For example, 100mcg of fluticasone propionate is approximately equivalent to 200mcg of beclomethasone dipropionate (CFC containing) or budesonide. If an individual patient should require dosages outside the recommended regimen, appropriate doses of beta-agonist and/or corticosteroid should be prescribed.
Recommended Doses:
Asthma
Adults and adolescents 12 years and older:
One inhalation of 250 micrograms of fluticasone propionate and 50 micrograms salmeterol twice daily, or
One inhalation of 500 micrograms of fluticasone propionate and 50 micrograms salmeterol twice daily.
A short term trial of Rolenium 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 one inhalation of 100 micrograms fluticasone propionate and 50 micrograms salmeterol 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.
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. Rolenium is not intended for the initial management of mild asthma. It is recommended to establish the appropriate dosage of inhaled corticosteroid before any fixed combination can be used in patients with severe asthma.
There are no data for the use of Rolenium in children below 12 years of age.
COPD
Adults:
One inhalation of 500 micrograms of fluticasone propionate and 50 micrograms of salmeterol 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 Rolenium in patients with hepatic impairment.

The management of asthma should normally follow a stepwise programme and patient response should be monitored clinically and by lung function tests.
Rolenium 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 medicinal product to be used for relief in an acute asthma attack available at all times.
Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of 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. The patient should also be medically reviewed where the current dosage of Rolenium has failed to give adequate control of asthma. For patients with asthma or COPD, consideration should be given to additional corticosteroid therapies.
Treatment with Rolenium should not be stopped abruptly in patients with asthma due to risk of exacerbation. Therapy should be down-titrated under physician supervision. For patients with COPD cessation of therapy may also be associated with symptomatic decompensation and should be supervised by a physician.
As with all inhaled medication containing corticosteroids, Rolenium should be administered with caution in patients with pulmonary tuberculosis.
Rarely, fluticasone propionate - salmeterol combination may cause cardiac arrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and a mild transient reduction in serum potassium at high therapeutic doses. Therefore Rolenium should be used with caution in patients with severe cardiovascular disorders, heart rhythm abnormalities, 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 after dosing. Rolenium should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.
Rolenium contains lactose approximately 24.5 milligram/dose. This should be considered by lactose intolerant people.
Care should be taken when transferring patients to Rolenium therapy, particularly if there is any reason to suppose that adrenal function is impaired from previous systemic steroid 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, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. 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.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroid is regularly monitored.
Prolonged treatment of patients with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children and adolescents <16 years taking high doses of fluticasone propionate (typically
1000mcg/day) may be at particular risk. Very rare cases of adrenal suppression and acute adrenal crisis have also been described with doses of fluticasone propionate between 500 and less than 1000mcg. Situations, which could potentially trigger acute adrenal crisis in patients, 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.
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. 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).

For patients with asthma, both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use.
Concomitant use of other beta-adrenergic containing drugs can have a potentially additive effect.
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, 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.

There are insufficient data on the use of fluticasone propionate and salmeterol during pregnancy and lactation in man to assess the possible harmful effects. In animal studies foetal abnormalities occur after administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (see section 5.3).
Administration of Rolenium to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.
The lowest effective dose of fluticasone propionate needed to maintain adequate asthma control should be used in the treatment of pregnant women.
There are no data available for human breast milk. Both fluticasone propionate and salmeterol are excreted into breast milk in rats. Administration of Rolenium to women who are breastfeeding should only be considered if the expected benefit to the mother is greater than any possible risk to the child.

No studies of the effect on the ability to drive and use machines have been performed.

As Rolenium contains fluticasone propionate and salmeterol, 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 fluticasone propionate/salmeterol are given below, listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100) and very rare (<1/10,000) including isolated reports. Very common, common and uncommon events were derived from clinical trial data. The incidence in placebo was not taken into account. Very rare events were derived from post-marketing spontaneous data.

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.
Due to the fluticasone propionate component, hoarseness and candidiasis (thrush) of the mouth and throat can occur in some patients. Both hoarseness and incidence of candidiasis may be relieved by gargling with water after using the product. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Rolenium.

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma (see section 4.4).
There have been very rare reports of hyperglycaemia (see section 4.4).
As with other inhalation therapy, paradoxical bronchospasm may occur (see section 4.4).

There are no data available from clinical trials on overdose with Rolenium, however data on overdose with both drugs are given below:
The signs and symptoms of salmeterol overdose are tremor, headache and tachycardia. The preferred antidotes are cardioselective beta-blocking agents, which should be used with caution in patients with a history of bronchospasm. If Rolenium 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 potassium supplemetation 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: Refer to section 4.4: risk of adrenal suppression. Monitoring of adrenal reserve may be necessary. In cases of fluticasone propionate overdose, Rolenium therapy may still be continued at a suitable dosage for symptom control.

Pharmacotherapeutic Group: Adrenergics and other anti-asthmatics.
ATC Code: R03AK06

Fluticasone propionate / Salmeterol Asthma clinical trials
A twelve month study (Gaining Optimal Asthma ControL, GOAL), in 3416 adult and adolescent patients with persistent asthma, compared the safety and efficacy of Fluticasone propionate /Salmeterol versus inhaled corticosteroid, ICS (Fluticasone Propionate) alone to determine whether the goals of asthma management were achievable. Treatment was stepped up every 12 weeks until **Total control was achieved or the highest dose of study drug was reached. GOAL showed more patients treated with Fluticasone propionate /Salmeterol achieved asthma control than patients treated with ICS alone and this control was attained at a lower corticosteroid dose.
Well Controlled asthma was achieved more rapidly with Fluticasone propionate /Salmeterol than with ICS alone. The time on treatment for 50% of subjects to achieve a first individual Well Controlled week was 16 days for Fluticasone propionate /Salmeterol compared to 37 days for the ICS group. In the subset of steroid naive asthmatics the time to an individual Well Controlled week was 16 days in the Fluticasone propionate /Salmeterol treatment compared to 23 days following treatment with ICS.
The overall study results showed:

*Well controlled asthma; occasional symptoms or SABA use or less than 80% predicted lung function plus no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy
**Total control of asthma; no symptoms, no SABA use, greater than or equal to 80% predicted lung function, no night-time awakenings, no exacerbations and no side effects enforcing a change in therapy
The results of this study suggest that Fluticasone propionate /Salmeterol 100/50mcg bd may be considered as initial maintenance therapy in patients with moderate persistent asthma for whom rapid control of asthma is deemed essential (see section 4.2).

A double-blind, randomised, parallel group study in 318 patients with persistent asthma aged ≥ 18 years evaluated the safety and tolerability of administering two inhalations twice daily (double dose) of Fluticasone propionate /Salmeterol for two weeks. The study showed that doubling the inhalations of each strength of Fluticasone propionate /Salmeterol for up to 14 days resulted in a small increase in beta-agonist-related adverse events (tremor; 1 patient [1%] vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps; 6[3%] vs 1 [<1%]) and a similar incidence of inhaled corticosteroid related adverse events (e.g. oral candidiasis; 6 [6%] vs 16 [8%], hoarseness; 2 [2%] vs 4 [2%]) compared to one inhalation twice daily. The small increase in beta-agonist-related adverse events should be taken into account if doubling the dose of Fluticasone propionate /Salmeterol is considered by the physician in adult patients requiring additional short-term (up to 14 days) inhaled corticosteroid therapy.

Fluticasone propionate /Salmeterol COPD clinical trials
Placebo-controlled clinical trials, over 6 and 12 months, have shown that regular use of Fluticasone propionate/Salmeterol 500/50 micrograms improves lung function and reduces breathlessness and the use of relief medication.
In 12 months the risk of acute exacerbations of COPD has been reduced from 1.42 per year to 0.99 per year in comparison with the placebo treatment and the risk of acute exacerbations requiring orally taken steroids has been significantly reduced from 0.81 to 0.47 per year compared to the placebo treatment.
Mechanism of action:
Rolenium contains salmeterol and fluticasone propionate which have differing modes of action. The respective mechanisms of action of both drugs are discussed below:
Fluticasone propionate:
Fluticasone propionate given by inhalation at recommended doses has a 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.
Salmeterol:
Salmeterol is a selective long-acting (12 hour) beta-2-adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.
Salmeterol produces a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting beta-2-agonists.

When fluticasone propionate and salmeterol were administered in combination by the inhaled route, the pharmacokinetics of each component were similar to those observed when the drugs were administered separately. For pharmacokinetic purposes therefore each component can be considered separately.
Fluticasone propionate:
The absolute bioavailability of inhaled fluticasone propionate in healthy subjects varies between approximately 10-30% of the nominal dose depending on the inhalation device used. In patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed.
Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.
The disposition of fluticasone propionate is characterised by high plasma clearance (1150ml/min), a large volume of distribution at steady-state (approximately 300l) and a terminal half-life of approximately 8 hours.

Fluticasone propionate is cleared very rapidly from the systemic circulation. The main pathway is metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450 enzyme CYP3A4. Other unidentified metabolites are also found in the faeces.
The renal clearance of fluticasone propionate is negligible. Less than 5% of the dose is excreted in urine, mainly as metabolites. The main part of the dose is excreted in faeces as metabolites and unchanged drug.
Salmeterol:
Salmeterol acts locally in the lung therefore plasma levels are not an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram /ml or less) achieved after inhaled dosing.

The only safety concerns for human use derived from animal studies of fluticasone propionate and salmeterol xinafoate given separately were effects associated with exaggerated pharmacological actions.
In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol xinafoate have shown embryofoetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities.

Lactose monohydrate.

Not applicable.

Store below 30°C.

Each medicine (fluticasone propionate and salmeterol) is packed separately from the other in one of the two blisters of the specially designed double-blister strip.
Each carton box contains one inhalation device Elpenhaler with 60 alu-alu double blister strips.

To ensure proper administration of the drug, the patient should be shown how to use the inhaler by a physician or other health professional.

The following are instructions to the patient for the proper inhalation of the two medicines packed in the two blisters of the single dose strips (double-blister strips), which are stored in the Elpenhaler.
DESCRIPTION
The Elpenhaler is a device for simultaneous inhalation of two medicines which are in the form of powder. The two medicines form in one medicinal combination. Each medicine is packed separately from the other in one of the two blisters of the specially designed double-blister strip.
The double-blister strip contains one (1) dose of the medicinal combination.
The Elpenhaler is comprised of 3 parts:
- The mouthpiece and its protective cover (1).
- The surface (2) on which the double-blister strip is placed (supporting surface).
- The storage compartment (3) which houses the double-blister strips.
The three parts are connected to each other and can be opened separately.
The supporting surface contains:
- An attachment point (2A) where the double- blister strip is attached.
- Two cavities (2B) which accommodate the two blisters of the strip.
- Two strip guides (2C) which firmly secure the double-blister strip in the correct position on the supporting surface.

The double blister strip contains:
- Two sheets (4).
- Two blisters (5), one containing salmeterol and the other fluticasone propionate.
- A hole (6).
USE OF THE Elpenhaler
Α. Preparing the device
Open the storage compartment, take a strip and close the storage compartment again.
Uncover the mouthpiece completely from its protective cover.
Unlock and push the mouthpiece backwards as to reveal the supporting surface.
Hold the double-blister strip with its shiny surface upwards. Place the strip on the attachment point of the supporting surface. By applying light pressure make sure the strip is securely attached on the attachment point.
The two blisters of the strip will fit in the cavities of the supporting surface, and the guides will guide the strip in the correct position.

Close the mouthpiece, and pull away the
protruding end of the strip.
The dose is now ready to be inhaled.

Β. Inhalation of the dose
Hold the device away from your mouth.
Exhale completely. Be careful not to exhale on the mouthpiece of the device.
Bring the Elpenhaler to your mouth and place your lips tightly around the mouthpiece.
Breathe in slowly and deeply from your mouth
(and not from your nose) until your lungs are
full.
Hold in your breath for approximately 5
seconds or as long as you comfortably can and
at the same time remove the device from your
mouth.
Exhale and continue to breathe normally.
Open the mouthpiece. You will notice that you
have inhaled all the powder and that the
blisters of the strip are empty.
Remove the empty strip, and proceed to step C.

C. Cleaning the device
Following each use, wipe the mouthpiece and the supporting surface with a dry cloth
or dry paper tissue. Do not use water to clean the device.
Close the mouthpiece and place the protective cover around it.