Cetirizin Mylan
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
CetirizinMylan 10 mgfilm-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Eachfilm-coated tablet contains 10 mg of cetirizinedihydrochloride.
Excipient with known effect:
Each film-coated tablet contains 74.3 mg lactosemonohydrate
Forthefull list ofexcipients, seesection 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet
White, capsuleshaped, film-coated tablet with breaklineand marked ‘CZ’and ‘10’on one sideand marked ‘G’on thereverse.
The tablet can be divided into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeuticindications
Cetirizin Mylan is indicated in adultsand childrenaged 6 yearand above:
- Forthereliefofnasaland ocularsymptomsofseasonaland perennial allergicrhinitis.
- Forthereliefofsymptomsofchronicidiopathicurticaria.
4.2 Posologyand method ofadministration
Posology
Children aged from6 to 12 years:5 mgtwicedaily(ahalftablettwicedaily).
Adults and adolescents over 12 years ofage:10 mgoncedaily(one tablet).
Older people:datado notsuggestthatthedoseneedsto bereduced in older people provided thattherenalfunction isnormal.
Paediatric population
Theuseofthefilm-coated tabletformulation isnotrecommended in children aged lessthan 6 years sincethisformulation doesnotallowforappropriatedoseadaptation.Patients with moderate to severe renalimpairment:
Thedosingintervalsmustbe individualised accordingto renalfunction. Referto thefollowingtableand adjustthedoseasindicated. To usethisdosingtable, an estimateofthepatient’screatinineclearance(CLcr) in ml/min is needed. TheCLcr(ml/min)maybeestimated fromserumcreatinine(mg/dl)determination usingthefollowingformula:
Dosingadjustments foradult patients with impaired renal function
|
Group Creatinine clearance (ml/min) Dosage and frequency |
|
Normal ≥ 80 10 mg once daily |
|
Mild 50 – 79 10 mg once daily |
|
Moderate 30 – 49 5 mg once daily |
|
Severe <30 5 mg once every 2 days |
|
End-stage renal disease - <10 Contra- indicated Patients undergoing dialysis |
In pediatricpatientssufferingfromrenalimpairment, thedosewillhaveto beadjusted on an individualbasistakinginto accounttherenalclearanceofthepatient, hisageand hisbody weight.
Patientswithhepaticimpairment:no doseadjustmentisneeded in patientswith solely hepaticimpairment.
Patientswithhepaticimpairmentand renalimpairment:doseadjustmentisrecommended
(see Patientswith moderateto severerenalimpairmentabove).
Method of administration
Thetabletsneed to beswallowed with aglassofliquid.
4.3 Contraindications
Hypersensitivityto the active substance or to anyoftheexcipients listed in section 6.1 or to hydroxyzineorto any piperazinederivatives.
Patientswith severerenalimpairmentatlessthan 10 ml/min creatinineclearance.
4.4 Specialwarningsand precautionsforuse
Attherapeuticdoses, no clinicallysignificantinteractionshavebeen demonstrated with alcohol(fora blood alcohollevelof0.5 g/L). Nevertheless, precaution isrecommended ifalcoholistaken concomitantly.
Caution should be taken in patients with predisposition factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as cetirizine may increase the risk of urinary retention.
Caution in epilepticpatientsand patientsatriskofconvulsionsisrecommended.
Allergyskin testsareinhibited byantihistaminesand awash-outperiod (of3 days)isrequired before performingthem.
Patientswith rarehereditaryproblemsofgalactoseintolerance, theLapp lactasedeficiencyor glucose-galactosemalabsorption should nottakeCetirizinMylan film-coated tablets.
4.5 Interaction with othermedicinalproductsand otherformsofinteraction
Dueto thepharmacokinetic, pharmacodynamicand toleranceprofileofcetirizine, no interactionsare expected with thisantihistamine. Actually, neitherpharmacodynamicnorsignificantpharmacokinetic
interaction wasreported in drug-druginteractionsstudiesperformed, notablywith pseudoephedrine ortheophylline(400 mg/day).
Theextentofabsorption ofcetirizineisnotreduced with food, although therateofabsorption is decreased.
4.6 Fertility, pregnancyand lactation
Pregnancy
Forcetirizinevery rareclinicaldataonexposedpregnanciesareavailable. Animalstudiesdo not indicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/fetaldevelopment, parturitionorpostnataldevelopment.Cautionshouldbeexercisedwhenprescribing topregnant women.
Breast-feeding
Cetirizineisexcreted in human milkatconcentrationsrepresenting0.25 to 0.90 thosemeasured in plasma, dependingon samplingtimeafter administration. Therefore, caution should beexercised when prescribingCetirizin Mylanto lactatingwomen.
4.7 Effectson abilityto driveand usemachines
Objectivemeasurementsofdrivingability, sleep latencyand assemblylineperformancehavenot demonstrated anyclinicallyrelevanteffectsattherecommended doseof10 mg.
Patients intending to drive, engaging in potentially hazardous activities or operatingmachinery shouldnotexceedtherecommendeddoseandshouldtaketheirresponsetothemedicinalproduct into account.
In thesesensitivepatients, concurrentusewith alcoholorotherCNS depressantsmaycause additionalreductionsin alertnessand impairmentofperformance.
4.8 Undesirableeffects
Clinicalstudieshaveshown thatcetirizineattherecommended dosagehasminorundesirableeffects on theCNS, includingsomnolence, fatigue, dizzinessand headache. In somecases, paradoxicalCNS stimulation hasbeen reported.
Although cetirizineisaselectiveantagonistofperipheralH1-receptors and isrelativelyfreeof anticholinergicactivity, isolated casesofmicturition difficulty, eyeaccommodation disordersand dry mouth havebeen reported.
Instancesofabnormalhepaticfunction with elevated hepaticenzymesaccompanied byelevated bilirubin havebeen reported. Mostlythisresolvesupon discontinuation ofthetreatmentwith cetirizinedihydrochloride.
a)Clinicaltrials
Doubleblind controlled clinicalorpharmacoclinicaltrialscomparingcetirizineto placebo orother antihistaminesattherecommended dosage(10 mgdailyforcetirizine), ofwhich quantified safety dataareavailable, included morethan 3200 subjectsexposed to cetirizine.
Fromthispooling, thefollowingadverseeventswerereported forcetirizine10 mgin theplacebo controlled trialsatratesof1.0 %orgreater:
|
Adverse event (WHO-ART) |
Cetirizine 10 mg (n= 3260) |
Placebo (n = 3061) |
|
Body as a whole – general disorders Fatigue |
1.63 % |
0.95 % |
|
Central and peripheral nervous system disorders Dizziness Headache |
1.10 % 7.42 % |
0.98 % 8.07 % |
|
Gastro-intestinal system disorders Abdominal pain Dry mouth Nausea |
0.98 % 2.09 % 1.07 % |
1.08 % 0.82 % 1.14 % |
|
Psychiatric disorders Somnolence |
9.63 % |
5.00 % |
|
Respiratory system disorders Pharyngitis |
1.29 % |
1.34 % |
Although statisticallymorecommon than underplacebo, somnolencewasmild to moderatein the majorityofcases. Objectivetestsasdemonstrated byotherstudieshavedemonstrated thatusualdaily activitiesareunaffected attherecommended dailydosein healthyyoungvolunteers.
Adversedrugreactionsatratesof1 %orgreaterin children aged from6 monthsto 12 years, included in placebo-controlled clinicalorpharmacoclinicaltrialsare:
|
Adverse drug reactions (WHO-ART) |
Cetirizine (n=1656) |
Placebo (n =1294) |
|
Gastro-intestinal system disorders Diarrhoea |
1.0 % |
0.6 % |
|
Psychiatric disorders Somnolence |
1.8 % |
1. 4 % |
|
Respiratory system disorders Rhinitis |
1.4 % |
1.1 % |
|
Body as a whole – general disorders Fatigue |
1.0 % |
0.3 % |
b)Post-marketingexperience
In addition to theadverseeffectsreported duringclinicalstudiesand listed above, isolated casesof thefollowingadversedrugreactionshavebeen reported in post-marketingexperience.
Undesirableeffectsaredescribed accordingto MedDRASystemOrganClassand byestimated frequencybased on post-marketingexperience.
Frequenciesaredefined asfollows:Verycommon (≥ 1/10);common (≥ 1/100 to < 1/10);uncommon (≥ 1/1,000 to < 1/100);rare(≥ 1/10,000 to < 1/1,000);veryrare(< 1/10,000);notknown (cannotbe estimated fromtheavailabledata)
Blood and lymphaticdisorders:
Veryrare:thrombocytopenia
Immunesystemdisorders:
Rare:hypersensitivity
Veryrare:anaphylacticshock
Metabolism & nutrition disorders
Not known:increased appetite
Psychiatricdisorders:
Uncommon:agitation
Rare:aggression, confusion, depression, hallucination, insomnia
Veryrare:tics
Not known:suicidal ideation
Nervoussystemdisorders:
Uncommon:paraesthesia
Rare:convulsions,
Veryrare:dysgeusia, dyskinesia, dystonia, syncope, tremor
Notknown:amnesia, memoryimpairment
Eyedisorders:
Veryrare:accommodation disorder, blurred vision, oculogyration
Ear and labyrinth disorders:
Not known:vertigo
Cardiacdisorders:
Rare:tachycardia
Gastro-intestinaldisorders:
Uncommon:diarrhoea
Hepatobiliarydisorders:
Rare:hepaticfunction abnormal(increased transaminases, alkalinephosphatase, γ-GTand bilirubin)
Skin and subcutaneoustissuedisorders:
Uncommon:pruritus, rash
Rare:urticaria
Veryrare:angioneuroticoedema, fixed drugeruption
Renaland urinarydisorders:
Veryrare:dysuria, enuresis
Not known: urinary retention
Generaldisordersand administration siteconditions:
Uncommon:asthenia, malaise
Rare:oedema
Investigations:
Rare:weightincreased
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. Healthcare professionals are asked to report any suspected adverse reactions via <to be completed nationally>.
4.9 Overdose
a)Symptoms
Symptomsobserved afteran overdoseofcetirizinearemainlyassociated with CNS effectsorwith effectsthatcould suggestan anticholinergiceffect.
Adverseeventsreported afteran intakeofatleast5 timestherecommended dailydoseare:
confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinaryretention.
b)Management
Thereisno known specificantidoteto cetirizine.
Should overdoseoccur, symptomaticorsupportivetreatmentisrecommended. Gastriclavageshould beconsidered followingingestion ofashortoccurrence.
Cetirizineisnoteffectivelyremoved bydialysis.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamicproperties
Pharmacotherapeuticgroup:Piperazinederivatives, ATCcode:R06AE07
Cetirizine, ahuman metaboliteofhydroxyzine, isapotentand selectiveantagonistofperipheralH1- receptors. In vitro receptorbindingstudieshaveshown no measurableaffinityforotherthan H1- receptors.
In addition to itsanti-H1 effect, cetirizinewasshown to displayanti-allergicactivities:atadoseof
10 mgonceortwicedaily, itinhibitsthelatephaserecruitmentofeosinophils, in theskin and conjunctivaofatopicsubjectssubmitted to allergen challenge.
Studiesin healthyvolunteersshowthatcetirizine, atdosesof5 and 10 mgstronglyinhibitsthewheal and flarereactionsinduced byveryhigh concentrationsofhistamineinto theskin, butthecorrelation with efficacyisnotestablished.
In a35-daystudyin children aged 5 to 12, no toleranceto theantihistaminiceffect(suppression of whealand flare)ofcetirizinewasfound. When atreatmentwith cetirizineisstopped afterrepeated administration, theskin recoversitsnormalreactivityto histaminewithin 3 days.
In asix-week, placebo-controlled studyof186 patientswith allergicrhinitisand concomitantmild to moderateasthma, cetirizine10 mgoncedailyimproved rhinitissymptomsand did notalter pulmonaryfunction. Thisstudysupportsthesafetyofadministeringcetirizineto allergicpatients with mild to moderateasthma.
In aplacebo-controlled study, cetirizinegiven atthehigh dailydoseof60 mgforseven daysdid not causestatisticallysignificantprolongation ofQTinterval.
Attherecommended dosage, cetirizinehasdemonstrated thatitimprovesthequalityoflifeof patientswith perennialand seasonalallergicrhinitis.
5.2 Pharmacokineticproperties
Thesteady-statepeakplasmaconcentrationsisapproximately300 ng/mland isachieved within
1.0 ± 0.5 h. No accumulation isobserved forcetirizinefollowingdailydosesof10 mgfor10 days.
Thedistribution ofpharmacokineticparameterssuch aspeakplasmaconcentration (Cmax)and area undercurve(AUC)isunimodalin human volunteers.
Theextentofabsorption ofcetirizineisnotreduced with food, although therateofabsorption is decreased. Theextentofbioavailabilityissimilarwhen cetirizineisgiven assolutions, capsulesor tablets.
Theapparentvolumeofdistribution is0.50 l/kg. Plasmaprotein bindingofcetirizineis93 ± 0.3 %. Cetirizinedoesnotmodifytheprotein bindingofwarfarin.
Cetirizinedoesnotundergo extensivefirstpassmetabolism. Abouttwo third ofthedoseareexcreted unchanged in urine. Theterminalhalf-lifeisapproximately10 hours.
Cetirizineexhibitslinearkineticsovertherangeof5 to 60mg.
Specialpopulations
Older people:Followingasingle10 mgoraldose, half-lifeincreased byabout50 %and clearance decreased by40 %in 16 elderlysubjectscompared to thenormalsubjects. Thedecreasein cetirizine clearancein theseelderlyvolunteersappeared to berelated to theirdecreased renalfunction.
Paediatric population:Thehalf-lifeofcetirizinewasabout6 hoursin children of6-12 years and 5 hoursin children 2-6 years. In infantsand toddlersaged 6 to 24 months, itisreduced to 3.1 hours
Renal impairment:Thepharmacokineticsofthedrugweresimilarin patientswith mild impairment(creatinineclearancehigherthan 40 ml/min)and healthyvolunteers. Patientswith moderaterenalimpairmenthad a3-fold increasein half-lifeand 70 %decreasein clearance compared to healthyvolunteers.
Patientson hemodialysis(creatinineclearancelessthan 7 ml/min)given asingleoral10 mgdoseof cetirizinehad a3-fold increasein half-lifeand a70 %decreasein clearancecompared to normals. Cetirizinewaspoorlycleared byhaemodialysis. Dosingadjustmentisnecessaryin patientswith moderateorsevererenalimpairment(seesection 4.2).
Hepaticimpairment:Patientswith chronicliverdiseases(hepatocellular, cholestatic, and biliarycirrhosis)given 10 or20 mgofcetirizineasasingledosehad a50 %increasein half-life alongwith a40 %decreasein clearancecompared to healthysubjects.
Dosingadjustmentisonlynecessaryin hepaticallyimpaired patientsifconcomitantrenalimpairment ispresent.
5.3 Preclinical safety data
Non-clinical datareveal no special hazard forhumans based on conventional studies ofsafety pharmacology, repeated dosetoxicity, genotoxicity, carcinogenicpotential, toxicityto reproduction.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:Lactosemonohydrate
Maizestarch, pregelatinised
PovidoneK29/32
Magnesiumstearate
Tabletcoat:
Talc,
Titaniumdioxide(E171)
Hypromellose5cP(E464)
Macrogol400
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Container – 2 years
Blister – 3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Polypropylenecontainerwith tamper-evident polyethylene cap: 30, 100, 250.
PVdCcoated PVCblisterwith aluminium foil lidding: 2, 7, 10, 14, 15, 20, 30, 50, 60, 90,
100, 100 (10x10x1)and 50 (50x1)unit-dose.
Thelegal categoryofeach pack sizewill bedetermined nationally.
Not all pack sizes may bemarketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETINGAUTHORISATIONHOLDER
[To becompleted nationally]
8 MARKETINGAUTHORISATIONNUMBER(S)
[To becompleted nationally]
9 DATEOFFIRSTAUTHORISATION/RENEWAL OFTHEAUTHORISATION
[To becompleted nationally]
10 DATEOFREVISIONOFTHETEXT
2014-09-18