ROACCUTANE 10 MG

טמרופ ןולע הז עבקנ ע " י דרשמ תואירבה ונכותו קדבנ רשואו בודילע ראוני 2011

ROACCUTANE ®

ISOTRETINOIN

Capsules 10mg and 20 mg

1. NAME OF THE MEDICINAL PRODUCT

Roaccutane 10 mg capsules

Roaccutane 20 mg capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Roaccutane 10 mg:

Eachsoftcapsule contains10 mg ofisotretinoin.

Roaccutane 20 mg:

Eachsoftcapsule contains20 mg ofisotretinoin.

Excipients: Containssoya bean oil (refined, hydrogenated and partiallyhydrogenated) and

sorbitol(E420). For a fulllist of excipients,seesection 6.1.

3. PHARMACEUTICAL FORM

Capsules, soft

10 mg capsules:

Oval, opaque, brown-red capsulesimprintedwithROA 10inblackink.

20 mg capsules:

Oval, opaque, brown-red and whitecapsulesimprinted with ROA 20inblackink.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of severecystic acnethatdoes not respond to other treatments.

4.2Posologyand methodof administration

Isotretinoinshould onlybe prescribed by orunder the supervision of physicianswith

expertisein the use of systemicretinoids for thetreatment of severe acneand a full

understanding of the risks ofisotretinoin therapy and monitoring requirements.

The capsulesshould be taken with food once or twice daily.

Adultsincluding adolescentsand the elderly:

Isotretinoin therapy should be startedat adose of 0.5 mg/kg daily. The therapeutic response

to isotretinoin andsomeof the adverseeffectsare dose-related and varybetween patients.

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This necessitatesindividual dosageadjustmentduring therapy. For mostpatients,the dose

ranges from 0.5-1.0 mg/kg per day.

Long-term remission and relapse ratesare moreclosely related to the total dose

administered than to either duration of treatment or daily dose. It has been shown that no

substantialadditional benefitisto beexpectedbeyond a cumulative treatment doseof 120-

150 mg/kg.The duration of treatment will dependon the individualdailydose. A treatment

course of 16-24 weeks is normallysufficient to achieve remission.

In the majority of patients, complete clearing of the acne isobtained with a single treatment

course. In the event of a definite relapse a further courseofisotretinoin therapymaybe

consideredusing thesame dailydose andcumulative treatment dose.As further

improvement of the acne can be observedup to8 weeks after discontinuation oftreatment, a

further courseof treatment should not be considered untilatleast thisperiod has elapsed.

Patientswithsevere renal insufficiency

In patientswithsevererenal insufficiency treatment shouldbe started at a lower dose(e.g.

10 mg/day).The dose should thenbe increased upto 1 mg/kg/day or until the patient is

receiving the maximumtolerated dose (seesection 4.4).

Children

Roaccutane isnotindicated for the treatment of prepubertalacne and is not recommended in

patientsless than 12 years of age due to a lackofdata on efficacyand safety.

Patients withintolerance

In patientswho showsevere intolerance to the recommended dose, treatment may be

continued ata lower dosewith the consequencesof a longer therapy duration and a higher

riskof relapse. Inorder to achieve the maximum possibleefficacy in these patients the dose

should normallybecontinued at thehighest tolerated dose.

4.3 Contraindications

Isotretinoin iscontraindicated inwomen who are pregnant or breastfeeding (seesection 4.6).

Isotretinoin iscontraindicated inwomen of childbearing potential unlessall oftheconditions

of the PregnancyPrevention Programme aremet (see section 4.4).

Isotretinoin isalsocontraindicated in patientswith hypersensitivity toisotretinoin or toanyof

the excipients. Roaccutane containssoyaoil, partiallyhydrogenated soyaoil,and

hydrogenated soya oil. Therefore, Roaccutaneiscontraindicated inpatientsallergicto

peanut or soya.

Isotretinoin isalsocontraindicated in patients

With hepatic insufficiency

With excessively elevatedblood lipidvalues

With hypervitaminosis A

Receiving concomitant treatment with tetracyclines (seesection 4.5).

4.4Specialwarnings and precautions for use

Pregnancy Prevention Programme

This medicinalproduct isTERATOGENIC

Isotretinoin iscontraindicated inwomen of childbearing potential unlessall ofthe following

conditionsof the PregnancyPrevention Programme are met:

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She hassevere acne (such asnodular or conglobate acne or acne atrisk ofpermanent

scarring) resistant to adequate courses of standard therapy with systemic anti-

bacterials and topicaltherapy (seesection 4.1).

She understands the teratogenicrisk.

She understands the need for rigorous follow-up,ona monthly basis.

She understands and accepts theneed for effective contraception, without interruption,

1 month before starting treatment, throughoutthe duration oftreatment and 1month

after the end of treatment. At least one and preferably two complementary formsof

contraception including a barrier method shouldbeused.

Evenif shehas amenorrhea she mustfollow allof the advice on effective

contraception.

She shouldbe capableof complying with effective contraceptivemeasures.

She is informed and understands the potentialconsequencesof pregnancyand the

need to rapidlyconsultifthere is a risk of pregnancy.

She understands the need and acceptsto undergopregnancy testing before, during

and 5 weeksafter the end of treatment.

She hasacknowledged that she hasunderstoodthe hazardsand necessary

precautionsassociated with the useof isotretinoin.

These conditionsalsoconcern women who are not currentlysexuallyactive unlessthe

prescriberconsidersthatthere are compelling reasonstoindicate that there isno riskof

pregnancy.

The prescriber must ensure that:

The patient complieswiththe conditions for pregnancy prevention aslisted above,

including confirmation that she hasanadequate level ofunderstanding.

The patient hasacknowledgedthe aforementionedconditions.

The patient hasused atleast one and preferablytwo methods of effective

contraception including a barrier method for atleast 1 monthprior to starting treatment

and iscontinuing to useeffective contraception throughout the treatment period and for

at least 1month after cessation of treatment.

Negative pregnancy test resultshave beenobtained before,during and 5 weeksafter

the end of treatment. The dates and results of pregnancy tests should bedocumented.

Contraception

Female patients mustbeprovidedwithcomprehensiveinformation on pregnancyprevention

and shouldbe referred for contraceptive adviceiftheyare not using effectivecontraception.

Asa minimum requirement, femalepatients at potential riskof pregnancymust useat least

one effective method of contraception. Preferably the patientshould use two complementary

forms ofcontraceptionincluding a barrier method. Contraception should becontinuedfor at

least1month after stopping treatment withisotretinoin, evenin patients with amenorrhea.

Pregnancytesting

According tolocal practice, medicallysupervised pregnancytestswith aminimum sensitivity

of 25mIU/mL are recommended to be performed inthe first 3daysof themenstrualcycle, as

follows.

Prior to starting therapy:

In order to exclude the possibilityofpregnancyprior to startingcontraception, itis

recommended that an initialmedically supervised pregnancy test shouldbe performed and

itsdate andresult recorded. In patients without regular menses, the timingof thispregnancy

test should reflect thesexual activityof the patient and shouldbe undertaken approximately

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3 weeksafter thepatient lasthad unprotectedsexualintercourse. The prescribershould

educatethe patient about contraception.

A medicallysupervised pregnancy test shouldalsobe performed duringthe consultation

when isotretinoinis prescribed orinthe 3 days prior to thevisit tothe prescriber, andshould

havebeen delayeduntilthe patient had been using effectivecontraception for at least1

month. Thistest shouldensure the patient isnotpregnant when she startstreatment with

isotretinoin.

Follow-up visits

Follow-upvisitsshould bearrangedat 28day intervals.Theneed for repeated medically

supervised pregnancy testseverymonth should be determined according to local practice

including considerationof the patient’ssexual activityand recent menstrual history (abnormal

menses, missed periodsor amenorrhea). Where indicated,follow-up pregnancy tests should

be performed onthe day of the prescribingvisit orin the 3 days prior to thevisit to the

prescriber.

End of treatment

Fiveweeksafter stoppingtreatment, womenshould undergo afinal pregnancy testto

exclude pregnancy.

Prescribing and dispensing restrictions

Prescriptionsof isotretinoin for women of childbearing potentialshould be limited to 30 days

of treatment and continuation of treatment requires anew prescription. Ideally, pregnancy

testing,issuing a prescription and dispensing ofisotretinoin should occur on the sameday.

Dispensingof isotretinoin should occur withinamaximum of7days of the prescription.

Male patients:

The available data suggestthat the level ofmaternal exposure from the semen of the

patientsreceivingisotretinoin,isnot of a sufficient magnitudeto be associatedwith the

teratogeniceffectsofisotretinoin.

Male patients should be reminded that they mustnot share their medication with anyone,

particularly notfemales.

Additional precautions

Patientsshould be instructed never togivethismedicinal product to another person, and to

return anyunused capsules to theirpharmacistatthe end oftreatment.

Patientsshould not donate blood during therapy and for 1 month followingdiscontinuation of

isotretinoin because of thepotential risk to the foetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers,pharmacists and patientsinavoiding foetalexposure to

isotretinoin the Marketing Authorisation Holderwill provide educationalmaterial to reinforce

the warningsabout the teratogenicity of isotretinoin, to provide advice oncontraception

before therapyisstarted and to provide guidanceon the needfor pregnancy testing.

Full patient information about the teratogenic risk and the strict pregnancy prevention

measuresas specifiedin the Pregnancy Prevention Programmeshouldbe given bythe

physician toall patients,both maleand female.

Psychiatric disorders

Depression,depressionaggravated, anxiety,aggressive tendencies, mood alterations,

psychoticsymptoms,andvery rarely, suicidal ideation, suicide attemptsand suicide have

been reported inpatients treated withisotretinoin(seesection 4.8). Particularcareneeds to

be takeninpatients witha history ofdepressionand all patients should be monitoredfor

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signs of depression and referredfor appropriate treatment ifnecessary. However,

discontinuation of isotretinoin may beinsufficient toalleviatesymptoms and therefore further

psychiatric orpsychologicalevaluation maybe necessary.

Skin and subcutaneous tissues disorders

Acute exacerbation of acne isoccasionallyseen during the initialperiod but thissubsides

withcontinued treatment, usuallywithin7-10 days, and usually doesnot require dose

adjustment.

Exposure to intensesunlight or to UV rays should beavoided. Where necessary a sun-

protection product with a highprotection factor ofatleast SPF 15 shouldbeused.

Aggressivechemicaldermabrasion andcutaneouslaser treatment should be avoided in

patientsonisotretinoin for a period of 5-6 monthsafter theend of the treatmentbecause of

the riskof hypertrophicscarringinatypicalareasand morerarelypostinflammatory hyper or

hypopigmentationin treated areas. Waxdepilation should beavoidedinpatientson

isotretinoin for at least aperiod of 6 monthsafter treatment because of the risk ofepidermal

stripping.

Concurrentadministration of isotretinoin withtopicalkeratolytic or exfoliative anti-acne

agents should beavoided as localirritationmayincrease (see section 4.5).

Patientsshould be advised to use a skinmoisturising ointment or creamand a lip balm from

the start of treatment asisotretinoinislikelyto cause dryness of the skin and lips.

There havebeen post-marketing reports of severeskin reactions (e.g. erythema multiforme

(EM), Stevens-Johnsonsyndrome (SJS) and toxic epidermal necrolysis (TEN)) associated

withisotretinoinuse. Asthese events maybe difficultto distinguish fromother skinreactions

that may occur (seesection4.8), patientsshouldbe advisedof the signsand symptomsand

monitoredclosely for severeskin reactions.If a severe skinreactionis suspected,

isotretinoin treatment should be discontinued.

Allergic reactions

Anaphylactic reactionshave been rarelyreported, in somecases afterprevioustopical

exposure toretinoids. Allergiccutaneous reactions are reported infrequently. Seriouscases

of allergicvasculitis, oftenwith purpura (bruisesand red patches) of the extremitiesand

extracutaneous involvement havebeen reported. Severe allergicreactionsnecessitate

interruptionof therapy andcarefulmonitoring.

Eye disorders

Dryeyes,corneal opacities, decreased nightvision and keratitisusually resolve after

discontinuation of therapy. Dry eyescan be helpedby the application of a lubricatingeye

ointment orbythe application of tearreplacement therapy. Intolerance tocontactlensesmay

occurwhichmaynecessitate the patient to wear glassesduring treatment.

Decreased nightvisionhas also been reported and the onset insome patients wassudden

(see section 4.7). Patients experiencingvisual difficultiesshould be referred for an expert

ophthalmological opinion.Withdrawal of isotretinoinmay be necessary.

Musculo-skeletal and connective tissue disorders

Myalgia, arthralgia andincreasedserum creatine phosphokinase valueshavebeenreported

in patients receiving isotretinoin, particularlyin those undertakingvigorous physicalactivity

(see section 4.8).

Bone changes includingprematureepiphysealclosure, hyperostosis, and calcification of

tendonsand ligamentshaveoccurred after several years of administration at very highdoses

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for treating disorders ofkeratinisation. The dose levels, durationof treatment and total

cumulativedose inthese patients generally farexceeded those recommended for the

treatment of acne.

Benign intracranial hypertension

Casesof benign intracranial hypertension havebeen reported, some ofwhich involved

concomitant use of tetracyclines (seesection 4.3 and section 4.5). Signs and symptomsof

benign intracranialhypertensioninclude headache,nausea and vomiting, visualdisturbances

and papilloedema.Patientswho develop benignintracranialhypertensionshoulddiscontinue

isotretinoin immediately.

Hepatobiliarydisorders

Liver enzymesshouldbechecked before treatment, 1 month after the start of treatment, and

subsequentlyat 3 monthlyintervals unlessmorefrequent monitoringisclinicallyindicated.

Transient and reversibleincreasesinliver transaminaseshave been reported. In many cases

these changes have been withinthe normal range and valueshavereturned to baseline

levelsduring treatment. However,inthe event ofpersistent clinically relevant elevation of

transaminase levels, reduction of the doseor discontinuationof treatment should be

considered.

Renal insufficiency

Renalinsufficiency and renalfailuredo not affectthe pharmacokinetics ofisotretinoin.

Therefore, isotretinoin can be givento patientswith renal insufficiency. However,itis

recommended that patients are started on a lowdose and titratedup to the maximum

tolerated dose (seesection 4.2).

Lipid Metabolism

Serumlipids(fastingvalues) shouldbe checkedbefore treatment, 1 monthafter the start of

treatment, and subsequentlyat 3monthlyintervals unlessmore frequent monitoringis

clinically indicated. Elevated serumlipidvaluesusuallyreturnto normal onreductionof the

dose or discontinuationoftreatment and may alsorespond todietarymeasures.

Isotretinoinhas been associated withan increasein plasma triglyceridelevels.Isotretinoin

should be discontinued if hypertriglyceridaemiacannot be controlled atan acceptablelevel or

if symptoms of pancreatitisoccur (seesection 4.8). Levels inexcessof 800mg/dL or

9mmol/L aresometimesassociatedwith acute pancreatitis, whichmay befatal.

Gastrointestinaldisorders

Isotretinoinhas been associated withinflammatory boweldisease (including regionalileitis)

in patients without a priorhistory of intestinaldisorders. Patients experiencingsevere

(hemorrhagic)diarrhoeashould discontinue isotretinoin immediately.

Fructose intolerance

Roaccutane containssorbitol.Patients with rare hereditary problemsof fructoseintolerance

should not take this medicine.

High Risk Patients

In patientswith diabetes, obesity,alcoholism ora lipidmetabolism disorder undergoing

treatment with isotretinoin, more frequent checks of serumvalues forlipidsand/or blood

glucosemaybe necessary. Elevatedfasting blood sugarshave been reported, andnew

cases of diabetes havebeen diagnosed duringisotretinointherapy.

4.5Interactionwithother medicinal products and other forms of interaction

Patientsshould not takevitamin A as concurrentmedication due to the riskof developing

hypervitaminosisA.

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Casesof benign intracranial hypertension (pseudotumor cerebri)havebeen reported with

concomitant use of isotretinoin and tetracyclines.Therefore, concomitant treatment with

tetracyclines mustbe avoided (seesection 4.3 and section 4.4).

Concurrentadministration of isotretinoin withtopicalkeratolytic or exfoliative anti-acne

agents should beavoided as localirritationmayincrease (see section 4.4).

4.6 Pregnancy and lactation

Pregnancyis an absolutecontraindication to treatmentwithisotretinoin (see section

4.3). If pregnancydoesoccur in spite ofthese precautions during treatmentwith

isotretinoin or in the month following,there is a great risk of verysevere and serious

malformation ofthe foetus.

The foetal malformations associated with exposure to isotretinoin include centralnervous

systemabnormalities(hydrocephalus, cerebellar malformation/abnormalities,microcephaly),

facialdysmorphia, cleft palate, external earabnormalities(absence of external ear, small or

absent external auditorycanals), eyeabnormalities(microphthalmia), cardiovascular

abnormalities(conotruncal malformationssuch as tetralogy ofFallot, transposition of great

vessels,septal defects),thymusgland abnormalityand parathyroidglandabnormalities.

There isalso an increased incidence of spontaneous abortion.

If pregnancy occursin a woman treated withisotretinoin,treatment must bestopped and the

patient should be referred toa physicianspecialisedor experiencedinteratology for

evaluation andadvice.

Lactation:

Isotretinoin ishighly lipophilic,therefore thepassage of isotretinoininto humanmilkisvery

likely.Due tothe potential for adverse effectsinthe child exposedvia mothers’milk, the use

of isotretinoin iscontraindicatedin nursingmothers.

4.7Effects on abilitytodrive and use machines

A number ofcases of decreased night vision have occurred during isotretinoin therapy and in

rare instances havepersistedafter therapy(seesection 4.4and section4.8). Because the

onset insome patientswassudden, patientsshould be advised of thispotentialproblem and

warned tobe cautiouswhen drivingor operating machines.

Drowsiness,dizzinessandvisualdisturbanceshave been reported very rarely.Patients

should be warnedthat if theyexperience these effects, theyshould not drive, operate

machinery ortake part inanyother activitieswhere the symptomscould put either

themselvesor othersat risk.

4.8 Undesirable effects

Some of theside effects associated with theuseof isotretinoinare dose-related. The side

effectsaregenerallyreversibleafteraltering thedose or discontinuationof treatment,

howeversome maypersistafter treatment hasstopped. The following symptoms are the

mostcommonlyreported undesirable effects withisotretinoin: dryness ofthe skin, drynessof

the mucosae e.g. of thelips(cheilitis), the nasalmucosa (epistaxis) and the eyes

(conjunctivitis).

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Infections:

Very Rare (≤1/10 000)

Gram positive(mucocutaneous) bacterialinfection

Blood and lymphaticsystem

disorders:

Very common (≥1/10)

Common (≥1/100, < 1/10)

Very Rare (≤1/10 000)

Anaemia, red blood cellsedimentation rateincreased,

thrombocytopenia, thrombocytosis

Neutropenia

Lymphadenopathy

Immune systemdisorders:

Rare (≥1/10000,< 1/1000)

Allergic skinreaction, anaphylacticreactions,

hypersensitivity

Metabolism andnutrition

disorders:

Very Rare (≤1/10 000)

Diabetesmellitus, hyperuricaemia

Psychiatricdisorders:

Rare (≥1/10000,< 1/1000)

Very Rare (≤1/10 000)

Depression,depressionaggravated, aggressive

tendencies,anxiety,mood alterations.

Abnormal behaviour, psychotic disorder,suicidal ideation

suicide attempt, suicide

Nervous system disorders:

Common (≥1/100, < 1/10)

Very Rare (≤1/10 000)

Headache

Benign intracranialhypertension,convulsions, drowsiness,

dizziness

Eyedisorders:

Very common (≥1/10)

Very Rare (≤1/10 000)

Blepharitis,conjunctivitis, dry eye, eye irritation

Blurredvision, cataract,colour blindness(colourvision

deficiencies), contactlensintolerance, cornealopacity,

decreasednightvision,keratitis, papilloedema (as sign of

benignintracranialhypertension), photophobia,visual

disturbances.

Ear and labyrinth disorders:

Very Rare (≤1/10 000)

Hearing impaired

Vascular disorders:

Very Rare (≤1/10 000)

Vasculitis(for exampleWegener’sgranulomatosis, allergic

vasculitis)

Respiratory,thoracicand

mediastinal disorders:

Common (≥1/100, < 1/10)

Very Rare (≤1/10 000)

Epistaxis, nasal dryness, nasopharyngitis

Bronchospasm (particularlyinpatientswith asthma),

hoarseness

Gastrointestinal disorders:

Very Rare (≤1/10 000)

Colitis, ileitis, drythroat, gastrointestinal haemorrhage,

haemorrhagicdiarrhoeaand inflammatory boweldisease,

nausea, pancreatitis (seesection 4.4)

Hepatobiliary disorders:

Very common (≥1/10)

Very Rare (≤1/10 000)

Transaminase increased (see section 4.4)

Hepatitis

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Skin and subcutaneoustissues

disorders:

Very common (≥1/10)

Rare (≥1/10000,< 1/1000)

Very Rare (≤1/10 000)

Cheilitis, dermatitis, dryskin,localised exfoliation, pruritus,

rash erythematous,skin fragility(risk of frictional trauma)

Alopecia

Acne fulminans, acne aggravated (acne flare),erythema

(facial), exanthema, hairdisorders, hirsutism, nail

dystrophy, paronychia, photosensitivity reaction,pyogenic

granuloma, skinhyperpigmentation, sweatingincreased

Erythema multiforme, Stevens-Johnson Syndrome, toxic

epidermalnecrolysis.

Musculo-skeletal andconnective

tissuedisorders:

Very common (≥1/10)

Very Rare (≤1/10 000)

Arthralgia, myalgia, backpain (particularlyinchildren and

adolescent patients)

Arthritis,calcinosis(calcification ofligaments and

tendons), epiphyses premature fusion, exostosis,

(hyperostosis), reducedbone density,tendonitis

Renaland urinarydisorders:

Very Rare (≤1/10 000)

Glomerulonephritis

Generaldisorders and

administration siteconditions:

Very Rare (≤1/10 000)

Granulationtissue (increased formation of), malaise

Investigations:

Very common (≥1/10)

Common (≥1/100, < 1/10)

Very Rare (≤1/10 000)

Blood triglyceridesincreased, high densitylipoprotein

decreased

Blood cholesterolincreased, blood glucoseincreased,

haematuria, proteinuria

Blood creatine phosphokinaseincreased

* cannot beestimated fromthe available data

The incidence ofthe adverse events wascalculated from pooled clinical trialdatainvolving

824 patients and from post-marketing data.

4.9 Overdose

Isotretinoin isa derivative of vitaminA. Althoughthe acute toxicityofisotretinoinis low, signs

of hypervitaminosisA could appear in casesof accidentaloverdose.Manifestationsof acute

vitamin A toxicityinclude severe headache, nausea orvomiting, drowsiness,irritabilityand

pruritus. Signs and symptomsof accidentalor deliberate overdosage with isotretinoin would

probably besimilar. These symptoms would be expected tobe reversible and to subside

without theneed for treatment.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeuticgroup: Retinoid for treatment of acne.

ATC code:D10B A01

Mechanism of action

Isotretinoin isa stereoisomer ofall-trans retinoic acid (tretinoin). The exact mechanism of

action ofisotretinoin has not yet been elucidatedindetail, but it has beenestablishedthat the

improvement observedin the clinicalpicture ofsevere acneis associatedwithsuppression of

sebaceousgland activityand a histologicallydemonstratedreductioninthe sizeof the

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sebaceousglands. Furthermore, a dermal anti-inflammatory effect of isotretinoinhas been

established.

Efficacy

Hypercornification of theepitheliallining of the pilosebaceous unit leads tosheddingof

corneocytes into the ductand blockage bykeratin and excess sebum. Thisis followedby

formation ofa comedoneand, eventually,inflammatory lesions. Isotretinoin inhibits

proliferationof sebocytesand appearsto actinacne byre-setting the orderly programof

differentiation. Sebum isa majorsubstrate for the growth ofPropionibacterium acnes so that

reduced sebum production inhibitsbacterialcolonisation of the duct.

5.2 Pharmacokinetic properties

Absorption

The absorption of isotretinoin from the gastro-intestinaltract isvariable and dose-linear over

the therapeuticrange. The absolutebioavailabilityof isotretinoin hasnotbeen determined,

since the compound isnot available as an intravenous preparation for human use,but

extrapolation from dog studieswould suggest a fairly low andvariablesystemic

bioavailability.When isotretinoinis taken with food, the bioavailabilityisdoubled relative to

fasting conditions.

Distribution

Isotretinoin isextensively bound to plasma proteins, mainlyalbumin(99.9%). The volume of

distribution of isotretinoin in man hasnot been determinedsince isotretinoin is not available

as an intravenouspreparation for human use. Inhumanslittle information isavailable on the

distribution of isotretinoin into tissue. Concentrationsofisotretinoininthe epidermisareonly

half of thosein serum. Plasmaconcentrations ofisotretinoinare about 1.7timesthoseof

whole blood due to poorpenetration of isotretinoin into red blood cells.

Metabolism

After oraladministrationofisotretinoin, three major metabolites havebeen identified in

plasma: 4-oxo-isotretinoin, tretinoin,(all-trans retinoic acid),and 4-oxo-tretinoin. These

metaboliteshaveshownbiological activityinseveral invitro tests.4-oxo-isotretinoin has

been shownina clinicalstudy to bea significantcontributor tothe activityofisotretinoin

(reductioninsebum excretion rate despite no effect onplasmalevels of isotretinoin and

tretinoin).Otherminor metabolitesincludesglucuronide conjugates.Themajor metabolite is

4-oxo-isotretinoinwith plasmaconcentrationsatsteadystate, that are 2.5 times higher than

those ofthe parent compound.

Isotretinoinand tretinoin(all-transretinoicacid)are reversiblymetabolised (interconverted),

and the metabolism of tretinoinis therefore linkedwith that ofisotretinoin.It has been

estimated that 20-30 %of an isotretinoindoseis metabolised by isomerisation.

Enterohepaticcirculationmay playa significant role inthe pharmacokinetics of isotretinoin in

man. Invitrometabolism studies have demonstrated that several CYPenzymesare involved

in the metabolism of isotretinoin to 4-oxo-isotretinoinand tretinoin. No singleisoformappears

to have a predominant role. Isotretinoin and itsmetabolitesdonot significantlyaffectCYP

activity.

Elimination

After oraladministrationofradiolabelled isotretinoin approximately equalfractionsof the

dose were recoveredinurine and faeces. Following oraladministration of isotretinoin, the

terminalelimination half-life of unchanged drugin patients with acne hasa meanvalue of 19

hours. The terminalelimination half-life of 4-oxo-isotretinoin is longer, witha meanvalue of

29 hours.

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Isotretinoin isa physiological retinoidandendogenous retinoidconcentrations are reached

withinapproximately twoweeksfollowing the end of isotretinointherapy.

Pharmacokinetics in special populations

Since isotretinoin is contraindicatedin patientswithhepaticimpairment, limited information

on the kinetics ofisotretinoin isavailable inthispatient population.Renal failure does not

significantlyreduce the plasmaclearance of isotretinoin or 4-oxo-isotretinoin.

5.3Preclinical safetydata

Acute toxicity

The acute oral toxicityofisotretinoin was determinedinvarious animalspecies.LD50is

approximately 2000mg/kg inrabbits, approximately3000 mg/kginmice, andover

4000 mg/kg in rats.

Chronic toxicity

A long-term studyin rats over2 years (isotretinoin dosage 2, 8 and 32 mg/kg/d) produced

evidence ofpartialhairloss and elevatedplasmatriglycerides inthe higher dose groups. The

side effect spectrum ofisotretinoin in the rodentthus closely resembles that of vitamin A, but

does notinclude the massivetissue and organ calcificationsobserved with vitamin Ainthe

rat. The livercell changes observedwithvitaminA didnot occur with isotretinoin.

All observedside effects ofhypervitaminosisAsyndromewere spontaneouslyreversible

after withdrawalofisotretinoin. Evenexperimentalanimalsina poor general state hadlargely

recoveredwithin1–2 weeks.

Teratogenicity

Likeother vitaminA derivatives, isotretinoin hasbeen shown in animal experimentsto be

teratogenicandembryotoxic.

Due to the teratogenicpotentialofisotretinoin there are therapeuticconsequencesfor the

administration towomen ofa childbearing age (see section4.3, section4.4, and section 4.6).

Fertility

Isotretinoin,in therapeutic dosages,doesnotaffect the number, motilityand morphologyof

sperm and doesnot jeopardisethe formationanddevelopment ofthe embryoon the part of

the men taking isotretinoin.

Mutagenicity

Isotretinoinhas not been shown tobe mutagenic inin vitroorinvivoanimal tests.

6. PHARMACEUTICAL PARTICULARS

6.1List of excipients

Capsule filling :

Beeswax,yellow;

Soya-bean oil,refined;

Soya-beanoil, hydrogenated;

Soya-bean oil,partiallyhydrogenated.

Capsule shell :

Gelatin;

Glycerol85%;

Karion 83 containingsorbitol,mannitol, hydrogenated hydrolysedstarch;

ROACCUTANE ® MoH Approved Prescribing Information

Capsuels10mg & 20mg January2011

Titaniumdioxide (E171);

Red iron oxide (E172).

Dryprintingink :

Shellac, modified;

Blackiron oxide (E172);

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4Special precautions for storage

Triplex (OPA/ALU/PVC) aluminiumblisters:

Do not storeabove30°C.

Store in theoriginalpackage andkeep blisterinthe outer carton inorder to protect from

moisture and light.

6.5Nature and contents of container

Triplex-aluminium blisterpackscontaining 30capsules

6.6Special precautions for disposal

Return anyunusedRoaccutane capsulesto the Pharmacist.

7. MARKETINGAUTHORISATIONHOLDER

Roche Pharmaceuticals(Israel) Ltd.,P.O. Box7543 Petach-Tikva 49170

8. MARKETINGAUTHORISATIONNUMBER(S)

Roaccutanecapsules10mg 069.22.22903.00

Roaccutanecapsules20mg 069.21.22904.00

9. MANUFACTURER

F. Hoffmann-La Roche Ltd., Basel,Switzerland.

Medicine:keep outofreach ofchildren

1143ROAC0111