Salmeson
1. NAME OF THEMEDICINALPRODUCT
.
Salmeson 50 microgram/250 microgram/dose inhalation powder, pre-dispensed.
Salmeson 50 microgram/500 microgram/dose inhalation powder, pre-dispensed.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each pre-dispensed dose of Salmesoncontains
50 micrograms of salmeterol (as salmeterol xinafoate) and 250 micrograms of
fluticasone propionate.
50 micrograms of salmeterol (as salmeterol xinafoate) and 500 micrograms of
fluticasone propionate.
Excipient with known effect:
24.677 mg of lactose per dose.
24.427 mg of lactose per dose.
Forthe full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Inhalation powder, pre-dispensed.
White powder.
Salmesoncontainstwo medicinespackedinthe two blistersof the single dose foil strips (double-blister strips), which are stored in the inhalation device Elpenhaler.
Each doseis pre-dispensed in one double-blisterstrip.
4. CLINICAL PARTICULARS
4.1 Therapeuticindications
Salmeson is indicated in adults only
Asthma
Salmeson is indicated in the regular treatment of asthmawhereuse ofa combination product (long-actingbeta-2-agonistand inhaled corticosteroid) is appropriate:
- Patients not adequatelycontrolled with inhaled corticosteroids and 'as needed' inhaled short actingbeta-2-agonist
or
- Patients alreadyadequatelycontrolled on both inhaled corticosteroid and long-acting beta-2-agonist.
Chronic ObstructivePulmonaryDisease(COPD)
Salmeson is indicated forthe symptomatictreatment of patients with COPD, with a FEV1<60%predicted normal (pre-bronchodilator)and a historyof repeated exacerbations, who havesignificant symptoms despiteregularbronchodilatortherapy.
4.2 Posology andmethodofadministration
Salmeson is forinhalation use only.
Patientsshould be madeawarethat Salmeson must beused dailyforoptimum benefit, evenwhen asymptomatic.
Patients should be regularlyreassessed bya doctor, so that thestrength of Salmesontheyare receivingremains optimal and is onlychanged on medicaladvice. The doseshould betitrated to thelowest doseat which effectivecontrol of symptoms is maintained. Wherethe control of symptoms ismaintained with thelowest strength of the combination giventwice dailythen thenext step could includea testof inhaled corticosteroid alone.As an alternative, patients requiringa longactingbeta-2-agonist could be titrated to Salmesongiven oncedailyif, in the opinion of the prescriber, it would be adequate to maintain diseasecontrol. In the event of oncedaily dosing when thepatienthas a historyof nocturnal symptoms thedose should be given at night and when the patient has a historyof mainlyday-time symptoms thedose should be given in the morning.
Patients should be giventhe strengthof Salmesoncontainingtheappropriate fluticasonepropionatedosagefor the severityof their disease. Prescribers should be awarethat, in patients with asthma, fluticasonepropionateis as effectiveas other inhaled steroids at approximatelyhalfthemicrogram dailydose.If an individual patient should requiredosages outside the recommended regimen,appropriate doses ofbeta-agonistand/or corticosteroid should be prescribed.
Recommended Doses:
Asthma
Adults:
One inhalation of 50 micrograms salmeteroland 250 micrograms fluticasone propionatetwice daily.
or
One inhalation of 50 micrograms salmeteroland 500 micrograms fluticasone propionate twicedaily.
A short term trial of Salmeson maybe considered as initial maintenance therapyin adults with moderate persistent asthma (defined as patients with daily symptoms, dailyrescueuseand moderate to severeairflow limitation) forwhom rapid control of asthmais essential.In thesecases, the recommended initial dose is one inhalation of 50 micrograms salmeterol and 100 micrograms fluticasonepropionate twicedaily. Oncecontrol of asthmais attained treatment should be reviewed and considerationgiven as to whetherpatients shouldbe stepped down to an inhaled corticosteroid alone. Regularreview ofpatients as treatment is stepped down is important.
A clear benefit has not been shown ascompared to inhaled fluticasonepropionate alone usedas initial maintenancetherapywhen oneor two of thecriteria ofseverity aremissing.Ingeneral inhaled corticosteroids remain thefirst line treatment for most patients.Salmeson is notintended for the initial management of mild asthma.
Salmeterol/flutikason propionate 50 microgram/100 micrograms strength is not appropriatein adults with severe asthma; it is recommended to establish the appropriatedosageof inhaled corticosteroid beforeanyfixed combination can beused in patients with severe asthma.
For dosages, which cannot be achieved with Salmeson, other strengths of salmeterol/fluticasone medicinal products are available.
COPD
Adults:
One inhalation of 50 micrograms salmeterol and500 micrograms fluticasone propionatetwice daily.
Special patientgroups:
Thereis no need to adjust thedose in elderlypatients or in thosewith renal impairment. There areno data availablefor use ofsalmeterol/fluticasone propionate in patients with hepaticimpairment.
Children and adolescents
Salmeson shouldnot be used in children and adolescents.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
4.4 Specialwarnings andprecautionsfor use
The management of asthma should normallyfollow a stepwise programmeand
patient response should bemonitored clinicallyand bylungfunction tests.
Salmeson should not be used to treat acuteasthmasymptoms for which a fast and short actingbronchodilator is required. Patients should be advised to havetheir medicinal product to beused for relief in an acuteasthmaattack available at all times.
Patients should notbe initiated on Salmeson duringan exacerbation,or if they havesignificantlyworseningor acutelydeterioratingasthma.
Serious asthma-related adverseevents and exacerbations mayoccurduring treatment with Salmeson. Patients should be askedto continuetreatment but to seek medical adviceif asthmasymptoms remain uncontrolled or worsenafter initiation on
Salmeson.
Increasinguseof short-actingbronchodilators to relievesymptoms indicates deterioration of control and patients should be reviewed bya physician.
Sudden and progressivedeterioration in control of asthmais potentiallylife threateningand the patient should undergo urgentmedical assessment. Consideration should be given to increasingcorticosteroid therapy.The patient should also be medicallyreviewed wherethe current dosageofSalmeson has failed to give adequatecontrol of asthma.
Onceasthmasymptoms arecontrolled, consideration maybe given to gradually reducingthe dose of Salmeson. Regular reviewof patients as treatment is stepped down is important. Thelowest effectivedose ofSalmeson should be used (seesection 4.2).
Forpatients with asthma orCOPD, considerationshould be given to additional corticosteroid therapies.
Treatment withSalmeson should not be stopped abruptlyin patients with asthmadue to risk of exacerbation. Therapyshould bedown-titrated underphysician supervision. Forpatientswith COPD cessation of therapymayalso be associated with symptomatic decompensation and should besupervised bya physician.
As with allinhaled medication containingcorticosteroids,Salmeson should be administered with caution in patients with pulmonarytuberculosis.
Rarely, Salmeson maycause cardiacarrhythmias e.g. supraventricular tachycardia, extrasystoles and atrial fibrillation, and amild transient reduction in serum potassiumat high therapeuticdoses. ThereforeSalmeson should beused with caution in patients with severe cardiovasculardisorders, heart rhythmabnormalities, diabetes mellitus, thyrotoxicosis, uncorrected hypokalaemiaor patients predisposed to low levels of serum potassium.
Therehavebeen veryrarereports of increases in bloodglucoselevels (seesection
4.8) and this should beconsidered when prescribingto patients with ahistoryof diabetes mellitus.
As with other inhalation therapyparadoxical bronchospasm mayoccurwith an immediate increasein wheezingafter dosing.Salmeson should be discontinued immediately,the patient assessedand alternativetherapyinstituted if necessary.
Careshould be takenwhen transferringpatients toSalmeson therapy, particularlyif thereis anyreason to suppose thatadrenalfunction is impaired from previous systemicsteroidtherapy.
Systemiceffects mayoccurwith anyinhaled corticosteroid, particularlyathigh doses prescribedfor longperiods. Theseeffectsaremuch less likelyto occur than with oral corticosteroids. Possible systemiceffects includeCushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density,cataract,glaucomaand more rarely, a rangeof psychological or behavioural effects includingpsychomotorhyperactivity,sleep disorders, anxiety, depression or aggression (particularlyin children).It is important, therefore, that the patientis reviewed regularlyand the dose of inhaledcorticosteroid is reduced to thelowest doseat which effectivecontrol of asthmais maintained.
Prolonged treatment of patients with high doses ofinhaled corticosteroidsmayresult in adrenal suppression and acute adrenalcrisis. Veryrarecases of adrenal suppression and acuteadrenal crisis havealso been describedwith doses of fluticasonepropionate between 500 and less than 1000 mcg. Situations, which could potentiallytrigger acute adrenalcrisis include trauma, surgery, infection or anyrapid reduction in dosage. Presentingsymptoms aretypicallyvagueand mayinclude anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, hypotension, decreasedlevel of consciousness, hypoglycaemia, and seizures. Additional systemiccorticosteroid cover should be considered duringperiods of stress or electivesurgery.
The benefits of inhaled fluticasonepropionatetherapyshould minimise the need for oral steroids, but patients transferring from oral steroids mayremainat risk of impaired adrenal reserve for aconsiderable time.Patients who haverequired high doseemergencycorticosteroid therapyin thepast mayalso be at risk. This possibility of residual impairment should always be bornein mind in emergencyandelective situations likelyto producestress, andappropriatecorticosteroid treatment must be
considered. Theextent ofthe adrenal impairment mayrequirespecialistadvicebefore electiveprocedures.
Ritonavir cangreatlyincreasetheconcentration of fluticasonepropionate in plasma. Therefore,concomitant useshould be avoided, unless thepotential benefit to the patient outweighs therisk of systemiccorticosteroid side-effects. Thereis also an
increased risk of systemicside effects when combiningfluticasonepropionate with other potent CYP3A inhibitors (seesection 4.5).
Therewas an increased reportingof lowerrespiratorytract infections (particularly pneumoniaand bronchitis) in the TORCH studyin patients with COPD receiving salmeterol/fluticasonepropionate 50/500micrograms bd compared with placebo as well as in studies SCO40043 and SCO1000250 comparing the lower non-approved COPD dose of Salmeterol/Fluticasone, 50/250 micrograms bd, to salmeterol 50 micrograms bd only (see section 4.8 and 5.1). A similar incidence of pneumonia in the salmeterol/ fluticasone propionate group was seen across all studies. In TORCH, 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 overlap. . Ifa patient with severeCOPD has experienced pneumonia the treatment withsalmeterol/fluticasonepropionate should be re-evaluated.
Data froma largeclinicaltrial (the Salmeterol Multi-CenterAsthma Research Trial, SMART) suggestedAfrican-American patients wereat increased risk of serious respiratory-related eventsor deaths when usingsalmeterol compared with placebo (seesection 5.1).It is not known ifthis was due topharmacogeneticor other factors. Patients of black Africanor Afro-Caribbeanancestryshould thereforebe asked to continuetreatment but toseek medicaladviceif asthmasymptoms remained uncontrolled or worsenwhilst usingSalmeson.
Concomitant use of systemicketoconazole significantlyincreases systemicexposure to salmeterol. This maylead to an increasein theincidenceof systemiceffects (e.g. prolongation in theQTcinterval and palpitations).Concomitant treatment with ketoconazole or otherpotent CYP3A4 inhibitors should thereforebe avoided unless the benefits outweigh the potentiallyincreasedrisk of systemicside effectsof salmeterol treatment (seesection 4.5).
Salmeson contains lactose. Patients with rarehereditaryproblems of galactose intolerance, the Lapp lactasedeficiencyor glucose-galactose malabsorptionshould
not takethis medicine.
4.5 Interaction with othermedicinal products and otherforms of interaction
Both non-selectiveand selectivebeta-blockers should be avoided unless thereare compellingreasons for their use.
Concomitant use of otherbeta-adrenergic containingdrugscan havea potentially additive effect.
FluticasonePropionate
Under normalcircumstances, low plasma concentrations of fluticasonepropionateare achievedafter inhaled dosing, due to extensivefirst pass metabolism and high systemicclearancemediated bycytochrome P450 3A4 in thegut and liver.Hence, clinicallysignificant druginteractions mediated byfluticasonepropionateare
unlikely.
Inan interaction studyin healthysubjects with intranasal fluticasonepropionate, ritonavir (ahighlypotent cytochrome P450 3A4 inhibitor) 100 mgb.i.d. increased the fluticasonepropionateplasma concentrations several hundred fold,resultingin markedlyreduced serumcortisol concentrations.Information about this interaction is lacking forinhaledfluticasonepropionate, but amarked increasein fluticasone propionateplasma levels is expected. Cases of Cushing's syndromeand adrenal suppression havebeen reported. The combinationshould be avoided unlessthe benefit outweighs the increasedrisk of systemicglucocorticoid side-effects.
Ina small studyin healthyvolunteers, the slightlyless potent CYP3A inhibitor ketoconazole increased theexposureof fluticasonepropionateaftera singleinhalation by150%. This resulted in a greater reduction of plasmacortisol as compared with fluticasonepropionatealone. Co-treatment with otherpotent CYP3A inhibitors, such as itraconazole, is also expected to increasethe systemic fluticasonepropionate exposureand the risk ofsystemicside-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 mgorallyoncedaily) and salmeterol (50 mcg inhaled twicedaily) in 15 healthysubjects for 7 daysresulted in a significant increase in plasma salmeterol exposure(1.4-fold Cmaxand 15-fold AUC). This maylead to an increasein theincidenceof othersystemiceffects of salmeterol treatment (e.g. prolongation of QTcinterval and palpitations) compared with salmeterol or ketoconazole treatmentalone (seeSection 4.4).
Clinicallysignificant effects werenot seen on blood pressure, heart rate, blood glucoseand blood potassiumlevels. Co-administration with ketoconazole did not increasethe elimination half-lifeof salmeterol or increasesalmeterol accumulation with repeat dosing.
The concomitant administration of ketoconazole should be avoided, unlessthe benefits outweigh the potentiallyincreasedrisk of systemicside effects of salmeterol treatment. Thereis likelyto be a similarrisk of interaction with other potent CYP3A4 inhibitors (e.g. itraconazole, telithromycin, ritonavir).
Moderate CYP 3A4 inhibitors
Co-administration of erythromycin(500mg orallythreetimes aday)and salmeterol (50mcginhaled twicedaily) in 15 healthysubjects for 6 days resulted in a small but non-statisticallysignificant increasein salmeterolexposure(1.4-fold Cmaxand 1.2- fold AUC). Co-administration with erythromycinwas not associatedwith anyserious adverseeffects.
4.6 Fertility, pregnancy and lactation
Pregnancy
A moderateamountof data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicityof salmeterol and fluticasonepropionate.Animal studies haveshown reproductivetoxicityafter administration of beta-2-adrenoreceptor agonists and glucocorticosteroids (seesection
5.3).
Administration of Salmeson to pregnant women should onlybe considered if the expected benefit to the mother is greater thananypossible risk to the foetus.
The lowest effectivedoseof fluticasonepropionate needed to maintain adequate asthmacontrol should beused in thetreatment of pregnant women.
Breastfeeding
It is unknown whethersalmeterol and fluticasonepropionate/metabolites areexcreted in human milk.
Studies haveshown that salmeterol and fluticasonepropionate, and their metabolites, areexcreted into themilkof lactatingrats.
A risk to breastfed newborns/infants cannot beexcluded. A decision must be made whetherto discontinuebreast-feedingor to discontinue Salmeson therapy taking into account thebenefit of breast-feedingforthe child and the benefitof therapyforthewoman.
Fertility
There are no data in humans. However, animal studies showed no effects of salmeterol or fluticasone propionate on fertility.
4.7 Effects on ability to drive and usemachines
No studies of the effect on the ability to drive and use machines have been performed
4.8 Undesirable effects
As Salmeson contains salmeterol and fluticasone propionate, the typeand
severityof adversereactions associated with eachof the compounds maybeexpected. Thereis no incidenceof additional adverseeventsfollowingconcurrent
administration of the two compounds.
Adverseevents which havebeenassociated with salmeterol/fluticasone propionate aregiven below, listed bysystem organclass and frequency. Frequencies aredefined as: verycommon (≥1/10), common(≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare(≥1/10,000 to <1/1000), veryrare(<1/10,000) and not known (cannot be estimated from the available data). Frequencies were derived from clinical trial data. Theincidencein placebo wasnot taken into account.
|
System Organ Class |
Adverse Event |
Frequency |
|
Infections & Infestations |
Candidiasis of the mouth and throat |
Common |
|
Pneumonia |
Common 1,3,5 |
|
|
Bronchitis |
Common 1,3 |
|
|
Immune System Disorders |
Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions |
Rare |
|
Angioedema (mainly facial and oropharyngeal oedema), |
Rare |
|
|
Respiratory symptoms (dyspnoea) |
Uncommon |
|
|
Respiratory symptoms (bronchospasm) |
Rare |
|
|
Anaphylactic reactions including anaphylactic shock |
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 |
Common3 |
|
Hyperglycaemia |
Rare4 |
|
|
Psychiatric Disorders |
Anxienty |
Uncommon |
|
Sleep disorder and behavioural changes, including psychomotor hyperactivity and irritability (predominantly in children) |
Rare |
|
|
Depression, aggression (predominantly in children) |
Not known |
|
|
Nervous System Disorders |
Headache |
Very Common1 |
|
Tremor |
Uncommon |
|
|
Eye Disorders |
Cataract, Glaucoma |
Rare4 |
|
Cardiac Disorders |
Palpitations |
Uncommon |
|
Tachycardia |
Uncommon |
|
|
Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystoles) |
Rare |
|
|
|
Angina pectoris |
Uncommon |
|
Respiratory, Thoracic & Mediastinal Disorders |
Nasopharyngitis |
Very Common2,3 |
|
Throat irritation |
Uncommon |
|
|
Hoarseness/dysphonia |
Common |
|
|
Sinusitis |
Common1, 3 |
|
|
Paradoxical bronchospasm |
Rare4 |
|
|
Skin and Subcutaneous Tissue Disorders |
Contusions |
Common1,3 |
|
Musculoskeletal & Connective Tissue Disorders |
Muscle Cramps |
Uncommon |
|
Traumatic fractures |
Common1,3 |
|
|
Arthralgia |
Common |
|
|
Myalgia |
Common |
1Reported commonly in placebo
2Reported very commonly in placebo
3Reported over 3 years in a COPD study
4See section 4.4
5See section 5.1
Description of selected reactions
The pharmacological sideeffects of beta-2-agonisttreatment, such as tremor, palpitations and headache, havebeen reported, but tend to be transient andreduce with regular therapy.
Due to thefluticasonepropionatecomponent, hoarseness and candidiasis(thrush)of the mouth and throat canoccurin some patients.Both hoarseness and incidenceof candidiasismaybe relieved bygarglingwith water after usingthe product. Symptomaticcandidiasiscan betreated with topical anti-fungal therapywhilst still continuingwith the Salmeson.
4.9 Overdose
There areno data available from clinical trials on overdosewith Salmeson, however data on overdosewith both drugs are givenbelow:
The signsand symptomsof salmeterol overdosearetremor, headacheand tachycardia. The preferred antidotes arecardioselectivebeta-blocking agents, which should be usedwith caution in patients with a historyof bronchospasm.IfSalmesontherapyhas to bewithdrawn dueto overdose of thebetaagonistcomponent of the drug,provision of appropriate replacement steroid therapyshould be considered. Additionally, hypokalaemiacan occurand potassiumreplacement should be considered.
Acute: Acute inhalation of fluticasonepropionatedoses in excess of those recommended maylead to temporarysuppression of adrenal function. This does not need emergencyaction as adrenal function is recovered in a few days, as verified by plasmacortisol measurements.
Chronic overdoseof inhaled fluticasonepropionate: Refer to section 4.4: risk of adrenal suppression: Monitoringof adrenalreservemaybe necessary.In cases of fluticasonepropionateoverdoseSalmeson therapymaystillbe continued at a suitable dosagefor symptomcontrol.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamicproperties
PharmacotherapeuticGroup: Adrenergics and other anti-asthmatics.
ATC Code: R03AK06
Mechanism of action:
Salmeson contains salmeterol and fluticasone propionate, which have differing modes of action. 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 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.
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.
Clinical efficacy and safety
Asthma clinical trials
A twelve month study(GainingOptimal Asthma ControL, GOAL), in 3416 adultand adolescent patients with persistent asthma,compared the safetyand efficacyof Salmeterol/Fluticasonepropionate versus inhaledcorticosteroid,ICS(Fluticasone Propionate)alone to determinewhetherthegoalsof asthmamanagementwere achievable. Treatment was stepped up every12 weeks until **Total control was achieved or thehighest dose of studydrugwas reached. GOALshowed morepatients treated with salmeterol/fluticasonepropionateachieved asthmacontrol thanpatients treated withICSalone and this control was attained at a lowercorticosteroid dose.
WellControlled asthmawas achieved more rapidlywithsalmeterol/fluticasone propionatethan withICSalone. Thetime on treatment for 50%of subjects to achieve a first individual WellControlled week was 16 days for salmeterol/fluticasone propionatecompared to 37 daysfor theICSgroup.In the subset of steroidnaive asthmatics the time to an individual WellControlled weekwas 16 days in the salmeterol/fluticasonepropionate treatment compared to 23 daysfollowing treatment with ICS.
The overallstudyresults showed:
|
Percentage of Patients Attaining *Well Controlled (WC) and **Totally Controlled (TC) Asthma over 12 months |
||||
|
Pre-Study Treatment |
Salmeterol/Fluticasone propionate |
Fluticasone propionate |
||
|
|
WC |
TC |
WC |
TC |
|
No ICS (SABA alone) |
78% |
50% |
70% |
40% |
|
Low dose ICS (≤500mcg BDP or equivalent/day) |
75% |
44% |
60% |
28% |
|
Medium dose ICS (500-1000 mcg BDP or equivalent/day) |
62% |
29% |
47% |
16% |
|
Pooled results across the 3 treatment levels |
71% |
41% |
59% |
28% |
*Wellcontrolledasthma;occasionalsymptomsorSABAuseorlessthan80%predictedlungfunction plusnonight-timeawakenings,noexacerbationsandnosideeffectsenforcinga changeintherapy
**Totalcontrolofasthma;nosymptoms,noSABAuse,greaterthanorequalto80%predictedlung function,nonight-timeawakenings,noexacerbationsandnosideeffectsenforcinga changeintherapy
The results of this studysuggest thatsalmeterol/fluticasonepropionate 50/100mcgbd maybeconsidered as initial maintenancetherapyin patients with moderatepersistent asthmafor whom rapid control of asthmais deemed essential (seesection4.2).
A double-blind, randomised, parallelgroupstudyin 318 patients with persistent asthmaaged
18years evaluated the safetyand tolerabilityof administering two inhalations twicedaily(double dose) of salmeterol/fluticasonepropionatefortwo weeks. Thestudyshowed that doublingthe inhalations of each strength of salmeterol/fluticasonepropionate forup to 14 days resulted in a smallincreasein beta-agonist-related adverseevents (tremor; 1 patient [1%]vs 0, palpitations; 6 [3%] vs 1 [<1%], muscle cramps;6[3%]vs 1 [<1%]) and asimilar incidenceof inhaled corticosteroid related adverseevents (e.g.
oral candidiasis; 6 [6%]vs 16 [8%],
hoarseness;2 [2%]vs 4 [2%]) compared to one inhalation twicedaily.
The small increasein beta-agonist-related adverseevents should be taken into account if
doublingthe dose of salmeterol/fluticasonepropionate is considered bythephysician in adult patients requiringadditional short-term (up to 14 days) inhaled corticosteroid therapy.
Salmeterol/Fluticasonepropionate COPD clinical trials
TORCH was a 3-year studyto assess theeffect of treatment with salmeterol/fluticasonepropionate50/500mcgbd, salmeterol 50mcgbd, fluticasone propionate(FP) 500mcgbd or placebo on all-causemortalityin patients with COPD. COPD patients with a baseline(pre-bronchodilator) FEV1<60%of predicted normal were randomised to double-blind medication. Duringthe study, patients were permitted usual COPD therapywith theexceptionof otherinhaledcorticosteroids, long actingbronchodilators and long-term systemiccorticosteroids. Survival status at
3 years was determinedforall patients regardlessof withdrawalfrom study medication. The primaryendpointwas reduction in all cause mortalityat 3years for salmeterol/fluticasone propionatevs Placebo.
|
|
Placebo N=1524 |
Salmeterol 50 N=1521 |
FP 500 N=1534 |
Salmeterol/FP 50/500 N=1533 |
|
All cause mortality at 3 years |
||||
|
Number of deaths (%) |
231 (15.2%) |
205 (13.5%) |
246 (16.0%) |
193 (12.6%) |
|
Hazard Ratio vs Placebo (Cls) P value |
N/A |
0.879 (0.73, 1.06) 0.180 |
1.060 (0.89, 1.27) 0.525 |
0.825 (0.68, 1.00) 0.0521 |
|
Hazard Ratio Salmeterol/FP |
N/A |
0.932 (0.77, 1.13) |
0.774 (0.64, 0.93) |
N/A |
|
50/500 vs components (Cls) P value |
|
0.481 |
0.007 |
|
|
1. Non significant P value after adjustment for 2 interim analyses on the primary efficacy comparison from a log-rank analysis stratified by smoking status |
||||
Therewas a trend towards improved survival in subjects treatedwithSalmeterol/Fluticasone propionatecompared with placebo over 3years however this did not achievethestatistical significancelevel p≤ 0.05.
The percentageof patients who died within 3 years due to COPD-relatedcauses was
6.0% forplacebo, 6.1% forsalmeterol, 6.9% for FP and 4.7% for salmeterol/fluticasonepropionate.
The mean number ofmoderate to severe exacerbations peryearwas significantly reducedwithsalmeterol/fluticasonepropionateas compared with treatmentwith salmeterol, FPand placebo (mean rate in the salmeterol/fluticasonepropionategroup
0.85 comparedwith 0.97 in the salmeterolgroup,0.93 in theFP group and1.13 in the placebo). This translatesto a reduction in therateof moderate to severeexacerbations of 25%(95% CI: 19% to 31%; p<0.001)comparedwith placebo, 12% compared with salmeterol (95% CI: 5% to 19%, p=0.002)and 9%compared with FP(95%CI: 1% to
16%, p=0.024). Salmeterol and FPsignificantlyreduced exacerbation ratescompared with placebo by15% (95%CI: 7% to 22%; p<0.001) and 18% (95%CI: 11% to 24%; p<0.001)respectively.
Health Related QualityofLife, as measured bytheSt George's Respiratory Questionnaire(SGRQ)was improved byallactivetreatments in comparison with placebo. Theaverageimprovement over threeyears forSalmeterol/Fluticasone propionatecompared with placebo was-3.1 units (95% CI:-4.1 to -2.1; p<0.001), compared with salmeterol was-2.2 units (p<0.001) and compared with FPwas 1.2 units (p=0.017). A 4-unitdecreaseis considered clinicallyrelevant.
The estimated 3-year probabilityof havingpneumonia reportedas an adverseevent was 12.3% forplacebo, 13.3%for salmeterol, 18.3% forFPand 19.6%for salmeterol/fluticasonepropionate (Hazardratio forsalmeterol/fluticasonepropionate vs placebo: 1.64, 95% CI: 1.33 to 2.01, p<0.001). Therewas no increasein pneumoniarelated deaths; deaths while on treatment that wereadjudicatedas primarilydueto pneumonia were7 forplacebo, 9 forsalmeterol, 13 for FPand 8 for salmeterol/fluticasonepropionate.Therewas no significant differencein probability of bonefracture(5.1% placebo, 5.1% salmeterol,5.4% FPand 6.3% salmeterol/fluticasonepropionate; Hazard ratio for salmeterol/fluticasonepropionate vs placebo: 1.22, 95% CI: 0.87 to 1.72, p=0.248.
Placebo-controlledclinical trials, over 6 and 12 months, haveshown that regularuse ofsalmeterol/fluticasonepropionate 50/500 micrograms improves lung function and reduces breathlessness and the useof relief medication.
Studies SCO40043 and SCO100250 were randomised, double-blind, parallel-group, replicate studies comparing the effect of salmeterol/fluticasone propionate 50/250 micrograms bd (a dose not licensed for COPD treatment in the European Union) with salmeterol 50 micrograms bd on the annual rate of moderate/severe exacerbations in subjects with COPD with FEV1 less than 50% predicted and a history of exacerbations. Moderate/ severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalisation.
The trials had a 4 week run-in period during which all subjects received open-label salmeterol/ FP 50/250 to standardize COPD pharmacotherapy and stabilise disease prior to randomisation to blinded study medication for 52 weeks. Subjects were randomised 1:1 to salmeterol/ FP 50/250 (total ITT n=776) or salmeterol (total ITT n=778). Prior to run-in, subjects discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled longacting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Subjects used salbutamol on an as-needed basis throughout the studies.
The results of both studies showed that treatment with salmeterol/fluticasone propionate 50/250 resulted in a significantly lower annual rate of moderate/severe COPD exacerbations compared with salmeterol (SCO40043: 1.06 and 1.53 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001; SCO100250: 1.10 and 1.59 per subject per year, respectively, rate ratio of 0.70, 95% CI: 0.58 to 0.83, p<0.001). Findings for the secondary efficacy measures (time to
first moderate/severe exacerbation, the annual rate of exacerbations requiring oral corticosteroids, and pre-dose morning (AM) FEV1) significantly favoured salmeterol/fluticasone propionate 50/250 micrograms bd over salmeterol. Adverse event profiles were similar with the exception of a higher incidence of pneumonias and known local side effects (candidiasis and dysphonia) in the salmeterol/fluticasone propionate 50/250 micrograms bd group compared with salmeterol. Pneumonia-related events were reported for 55 (7%) subjects in the salmeterol/fluticasone propionate 50/250 micrograms bd group and 25 (3%) in the salmeterol group. The increased incidence of reported pneumonia with salmeterol/fluticasone 50/250 micrograms bd appears to be of similar magnitude to the incidence reported following treatment with salmeterol/fluticasone propionate 50/500 micrograms bd in TORCH.
The Salmeterol Multi-centerAsthmaResearch Trial (SMART)
SMART was a multi-centre, randomised, double-blind, placebo-controlled, parallel group28-week studyin theUS which randomised13,176 patients to salmeterol (50μg twice daily) and 13,179 patients to placebo in addition to thepatients'usualasthma therapy. Patients wereenrolled if 12 years of age,with asthma and if currentlyusing asthmamedication (but not a LABA). BaselineICSuse at studyentrywas recorded, but not required in thestudy. The primaryendpoint in SMART was the combined number of respiratory-related deaths andrespiratory-related life-threatening experiences.
Key findings from SMART: primary endpoint
|
Patient group |
Number of primary endpoint events/number of patients |
Relative Risk (95% confidence intervals) |
|
|
|
salmeterol |
placebo |
|
|
All patients |
50/13176 |
36/13179 |
1.4 0(0.91, 2.14) |
|
Patients using inhaled steroids |
23/6127 |
19/6138 |
1.21 (0.66, 2.23) |
|
Patients not using inhaled steroids |
27/7049 |
17/7041 |
1.60 (0.87, 2.93) |
|
African-American patients |
20/2366 |
5/2319 |
4.10 (1.54, 10.90) |
(Risk in bold is statisticallysignificant at the 95%level.)
Keyfindings from SMART byinhaled steroid use at baseline: secondaryendpoints
|
|
Number of secondary endpoint events/number of patients |
Relative Risk (95% confidence intervals) |
|
|
|
salmeterol |
placebo |
|
|
Respiratory-related death |
|||
|
Patients using inhaled steroids |
10/6127 |
5/6138 |
2.01 (0.69, 5.86) |
|
Patients not using inhaled steroids |
14/7049 |
6/7041 |
2.28 (0.88, 5.94) |
|
Combined asthma-related death or life-threatening experience |
|||
|
Patients using inhaled steroids |
16/6127 |
13/6138 |
1.24, (0.60, 2.58) |
|
Patients not using inhaled steroids |
21/7049 |
9/7041 |
2.39 (1.10, 5.22) |
|
Asthma-related death |
|||
|
Patients using inhaled steroids |
4/6127 |
3/6138 |
1.35 (0.30, 6.04) |
|
Patients not using inhaled steroids |
9/7049 |
0/7041 |
* |
(*=couldnotbecalculatedbecauseofnoeventsinplacebogroup.Riskinboldfiguresisstatistically significantatthe95%level.Thesecondaryendpointsinthetableabovereachedstatisticalsignificance inthewholepopulation.)Thesecondaryendpointsofcombinedall-causedeathorlife-threatening experience,allcausedeath,orallcausehospitalisationdidnotreachstatisticalsignificanceinthe wholepopulation.
5.2 Pharmacokineticproperties
When salmeteroland fluticasonepropionate wereadministered in combination bythe inhaled route, the pharmacokinetics of each component weresimilar to thoseobserved when the drugswere administered separately. For pharmacokinetic purposes therefore eachcomponent can beconsidered separately.
Salmeterol:
Salmeterol acts locallyin the lungthereforeplasmalevels arenot an indication of therapeuticeffects.In addition thereareonlylimited data available on the pharmacokinetics of salmeterol because of thetechnical difficultyof assayingthe drugin plasma dueto thelow plasma concentrations at therapeuticdoses
(approximately200 picogram /mlor less) achieved after inhaleddosing. Fluticasonepropionate:
The absolute bioavailabilityof a single dose of inhaled fluticasonepropionate in healthysubjects varies betweenapproximately5-11%of the nominal dose depending on the inhalation deviceused. In patients with asthma or COPD a lesser degreeof systemicexposureto inhaled fluticasonepropionate has been observed.
Systemicabsorption occurs mainlythrough the lungs and is initiallyrapid then prolonged. The remainder of the inhaled dose maybe swallowed but contributes minimallyto systemicexposuredue to thelow aqueous solubilityand pre-systemic metabolism, resultingin oral availabilityof less than 1%. Thereis a linear increasein systemicexposurewith increasinginhaled dose.
The disposition of fluticasonepropionateis characterised byhigh plasma clearance (1150ml/min), a largevolumeof distribution at steady-state(approximately300l) and aterminal half-lifeof approximately8 hours.
Plasmaprotein bindingis 91%.
Fluticasonepropionate is cleared very rapidlyfrom thesystemiccirculation. The main pathwayis metabolism to an inactivecarboxylicacid metabolite, bythe cytochrome P450 enzymeCYP3A4. Other unidentified metabolites arealso found in thefaeces.
The renal clearanceof fluticasonepropionate is negligible.Less than 5%of thedose is excreted in urine, mainlyas metabolites. Themain part ofthe dose isexcreted in faeces as metabolites andunchanged drug.
5.3 Preclinical safety data
The onlysafetyconcerns forhuman use derived from animal studies of salmeterol xinafoate and fluticasonepropionategiven separatelywere effects associated with exaggerated pharmacological actions.
Inanimal reproduction studies, glucocorticosteroids havebeen shown to induce malformations (cleft palate,skeletal malformations). However, theseanimal experimental results do not seem to be relevant for man givenrecommended doses. Animal studies with salmeterol xinafoate haveshown embryofoetal toxicityonlyat high exposurelevels.Followingco-administration, increased incidences of transposed umbilical arteryand incomplete ossification of occipital bone werefound in rats at doses associated with known glucocorticoid-induced abnormalities.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate.
6.2 Incompatibilities
Not applicable.
6.3 Shelflife
2 years.
6.4 Specialprecautionsfor storage
Storebelow 25 °C.
6.5 Natureandcontentsof container
Salmeson contains two medicines packed in the two alu-alu blistersof the single dose foil strips (double-blister strips), which are stored in the inhalation device Elpenhaler.
The foil protects the powder for inhalation from the effects of the atmosphere.
Each dose is pre-dispensed in one double-blisterstrip.
Each carton box contains one inhalation device Elpenhalerwith 60 double blister strips. 60 doses per pack.
Each carton box contains one inhalation device Elpenhalerwith 30 alu-alu double blister strips and one spare storage compartment with 30 additional alu-alu double blister strips. 60 doses per pack.
Each carton box contains one inhalation device Elpenhaler with 30 alu-alu double blister strips. 30 doses per pack (sample pack).
Each carton box contains three inhalation devices Elpenhaler with 60 alu-alu double blister strips each. 180 doses per pack.
Not all pack sizes may be marketed
6.6 Specialprecautionsfordisposal andotherhandling
To ensureproperadministrationof thedrug,the patientshould beshown howto use the inhalerbya physician or otherhealth professional.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
INSTRUCTIONS FOR USEAND HANDLING OFTHEElpenhaler
The followingareinstructionsto thepatientfor theproperinhalationof the two medicinespackedin thetwo blistersof the singledose strips(double-blister strips), which arestored in the Elpenhaler.
DESCRIPTION
The Elpenhaleris adevicefor inhalingatthe sametimetwo medicineswhicharein the formof powder.The twomedicinesformin one medicinalcombination.Each medicineis packedseparately fromthe otherin oneof thetwo blistersof thespecially designeddouble-blisterstrip.
The double-blisterstrip contains one(1) doseof themedicinal 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 blisterstripcontains:
- Twosheets (4).
- Twoblisters (5), one containingsalmeterol and the other fluticasonepropionate.
- A hole(6).
USE OFTHEElpenhaler
Α. Preparing the device
Open the storagecompartment, takea strip, and close the storagecompartment again.
- Uncover the mouthpiececompletelyfrom its protectivecover.
-
Unlock and push the mouthpiecebackwardsas to reveal the
supportingsurface.
- Hold the double-blisterstrip with its shinysurfaceupwards.
- Placethe strip on the attachment point of the supporting surface.By applyinglightpressuremake surethestrip is securelyattachedon theattachment point.
- The twoblistersof thestrip willfit inthe cavitiesof the supportingsurface,andthe guideswill securethestrip inthe correct position.
-Close themouthpiece,andpull awaytheprotrudingend of the strip. The dose is now ready to be inhaled. Pulling away the protruding end should only be done immediately before inhalation.
Β. Inhalationofthedose
Hold the deviceawayfromyour mouth.
- Exhale completely.Becareful not to exhale on the mouthpieceof the device.
- Bringthe Elpenhalerto your mouth and placeyourlips tightlyaroundthe mouthpiece.
- Breathe in slowlyand deeplyfromyour mouth (and not fromyour nose) untilyour lungs arefull.
- Hold inyour breath approximately5 seconds or as long as you comfortablycan andat thesame time removethe devicefromyour mouth.
- Exhale and continue to breathe normally.
- Openthe mouthpiece.You willnoticethat youhave inhaledallthe powderandthat theblistersof thestrip areempty.
- Remove the emptystrip,and proceed to step C.
C. Cleaning the device
- Following each use,wipethe mouthpieceand thesupportingsurfacewith adrycloth or drypaper tissue. Do not use waterto clean the device.
- Close the mouthpieceand placethe protectivecover aroundit.
7. MARKETINGAUTHORISATION HOLDER
<To becompleted nationally>
8. MARKETINGAUTHORISATION NUMBER(S)
<To becompleted nationally>
9. DATE OF FIRSTAUTHORISATION/ RENEWAL OFTHE AUTHORISATION
2013-03-13
10. DATE OF REVISION OF THETEXT
2013-03-13
17