Summary of product characteristics

Summary of Product Characteristics
NAME OF THE MEDICINAL PRODUCT

Isotretinoin 5 mg capsules
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soft capsule contains 5 mg of isotretinoin.
Excipients:
Soya-bean oil, refined 66,40 mg
Soya-bean oil, partly hydrogenated 3,850 mg
Sorbitol, liquid (non-crystallising) (E420) 4,995 mg
For the full list of excipients, see section 6.1.

3.
PHARMACEUTICAL FORM

Capsule, soft
Faint pinkish/cream to cream coloured oval, soft-gelatin capsules, containing a yellow/orange, opaque, viscous
liquid.

4.
CLINICAL PARTICULARS
Therapeutic indications

Severe forms of acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to
adequate courses of standard therapy with systemic antib acterials and topical therapy.

4.2
Posology and method of administration
Isotretinoin should only be prescribed by or under the supervision of physicians with expertise in the use of systemic retinoids for the treatment of severe acne and a full understa nding of the risks of isotretinoin therapy and monitoring requirements. Posology Adults including adolescents and the elderly: Isotretinoin therapy should be started at a dose of 0.5 mg/kg daily. The therapeutic response to isotretinoin and some of the adverse effects are dose-related and vary between patients. This necessitates individual dosage adjustment during therapy. For most patients, the dose ranges from 0.5-1.0 mg/kg per day. Long-term remission and relapse rates are more closely related to the total dose administered than to either duration of treatment or daily dose. It has been shown that no substantial additional benefit is to be expected beyond a cumulative treatment dose of 120-150 mg/kg. The duration of treatment will depend on the individual daily dose. A treatment course of 16-24 weeks is normally sufficient to achieve remission. In the majority of patients, complete clearing of the acne is obtained with a single treatment course. In the event of a definite relapse a further course of isotretinoin therapy may be considered using the same daily dose and cumulative treatment dose. As further improvement of the acne can be observed up to 8 weeks after discontinuation of treatment, a further course of treatment should not be considered until at least this period has elapsed. Patients with severe renal insufficiency In patients with severe renal insufficiency treatment should be started at a lower dose (e.g. 10 mg/day). The dose should then be increased up to 1 mg/kg/day or until the patient is receiving the maximu m tolerated dose (see section 4.4). Paediatric population Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in patients less than 12 years of age due to a lack of data on efficacy and safety. Patients with intolerance
In patients who show severe intolerance to the recommended dose, treatment may be continued at a lower dose
with the consequences of a longer therapy duration and a higher risk of relapse. In order to achieve the maximu m
possible efficacy in these patients the dose should normally be continued at the highest tolerated dose.

Method of administration
The capsules should be taken with food once or twice daily.

4.3
Contraindications
Isotretinoin is contraindicated in women who are pregnant or breastfeeding (see section 4.6). Isotretinoin is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met (see section 4.4). Isotretinoin is contraindicated in patients with hypersensitivity to isotretionin, soya, peanut or to any of the excipients. Isotretinoin is also contraindicated in patients  with excessively elevated blood lipid values receiving concomitant treatment with tetracyclines (see section 4.5) Special warnings and precautions for use

Pregnancy Prevention Programme

This medicinal product is TERATOGENIC
Isotretinoin is contraindicated in women of childbearing potential unless all of the following conditions of the
Pregnancy Prevention Programme are met:

She has severe acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy (see section 4.1). She understands the need for rigorous follow-up, on a monthly basis. She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the duration of treatment and 1 month after the end of treatment. At least one and preferably two complementary forms of contraception including a barrier method should be used. Even if she has amenorrhea she must follow all of the advice on effect ive contraception. She should be capable of complying with effective contraceptive measures. She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy. She understands the need and accepts to undergo pregnancy testing before, during and 5 weeks after the end of treatment. She has acknowledged that she has understood the hazards and necessary precautions associated with the These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy. The prescriber must ensure that:  The patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding. The patient has acknowledged the aforementioned conditions. The patient has used at least one and preferably two methods of effective contraception including a ba rrier method for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 1 month after cessation of treatment. Negative pregnancy test results have been obtained before, during and 5 weeks after the end of treatment. The dates and results of pregnancy tests should be documented.
Contraception
Female patients must be provided with comprehensive information on pregnancy prevention and should be
referred for contraceptive advice if they are not using effective contraception.
As a minimum requirement, female patients at potential risk of pregnancy must use at least one effective method
of contraception. Preferably the patient should use two complementary forms of contrace ption including a barrier
method. Contraception should be continued for at least 1 month after stopping treatment with isotretinoin, even
in patients with amenorrhea.
Pregnancy testing
According to local practice, medically supervised pregnancy tests wit h a minimum sensitivity of 25 mIU/mL are
recommended to be performed in the first 3 days of the menstrual cycle, as follows.
Prior to starting therapy:
In order to exclude the possibility of pregnancy prior to starting contraception, it is recommended t hat an initial
medically supervised pregnancy test should be performed and its date and result recorded. In patients without
regular menses, the timing of this pregnancy test should reflect the sexual activity of the patient and should be
undertaken approximately 3 weeks after the patient last had unprotected sexual intercourse. The prescriber
should educate the patient about contraception.
A medically supervised pregnancy test should also be performed during the consultation when isotretinoin is
prescribed or in the 3 days prior to the visit to the prescriber, and should have been delayed until the patient had
been using effective contraception for at least 1 month. This test should ensure the patient is not pregnant when
she starts treatment with isotretinoin.
Follow-up visits
Follow-up visits should be arranged at 28 day intervals. The need for repeated medically supervised pregnancy
tests every month should be determined according to local practice including consideration of the patient's sexual
activity and recent menstrual history (abnormal menses, missed periods or amenorrhea). Where indicated,
follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the
visit to the prescriber.
End of treatment
Five weeks after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.
Prescribing and dispensing restrictions
Prescriptions of isotretinoin for women of childbearing potential should be limited to 30 days of treatment and
continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and
dispensing of isotretinoin should occur on the same day. Dispensing of isotretinoin should occur within a
maximu m of 7 days of the prescription.
Male patients:
The available data suggest that the level of maternal exposure from the semen of the patients receiving
isotretinoin, is not of a sufficient magnitude to be associated with the teratogenic effects of isotretinoin. Male
patients should be reminded that they must not share their medication with anyone, particularly not females.
Additional precautions
Patients should be instructed never to give this medicinal product to another person and to return any unused
capsules to their pharmacist at the end of treatment.
Patients should not donate blood during therapy and for 1 month following discontinuation of isotretinoin
because of the potential risk to the foetus of a pregnant transfusion recipient.
Educational material
In order to assist pres cribers, pharmacists and patients in avoiding foetal exposure to isotretinoin the Marketing
Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of
isotretinoin, to provide advice on contraception before therapy is started and to provide guidance on the need for
pregnancy testing.

Full patient information about the teratogenic risk and the strict pregnancy prevention measures as specified in
the Pregnancy Prevention Programme should be given by the phys ician to all patients, both male and female.
Psychiatric disorders
Depression, depression aggravated, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and
very rarely, suicidal ideation, suicide attempts and suicide have been reporte d in patients treated with isotretinoin
(see section 4.8). Particular care needs to be taken in patients with a history of depression and all patients should
be monitored for signs of depression and referred for appropriate treatment if necessary. However,
discontinuation of isotretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or
psychological evaluation may be necessary.
Skin and subcutaneous tissue disorders
Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued
treatment, usually within 7 - 10 days, and usually does not require dose adjustment.
There have been post-marketing reports of severe skin reactions (e.g. erythema multiforme (EM), Stevens -
Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) associated with isotretinoin use. As these events
may be difficult to distinguish from other skin reactions that may occur (see section 4.8), patients should be
advised of the signs and symptoms and monitored clo sely for severe skin reactions. If a severe skin reaction is
suspected, isotretinoin treatment should be discontinued.
Exposure to intense sunlight or to UV rays should be avoided. Where necessary a sun -protection product with a
high protection factor of at least SPF 15 should be used.
Aggressive chemical dermabrasion and cutaneous laser treatment should be avoided in patients on isotretinoin
for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypica l
areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be
avoided in patients on isotretinoin for at least a period of 6 months after treatment because of the risk of
epidermal stripping.
Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-acne agents should be
avoided as local irritation may increase (see section 4.5).
Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the st art of treatment
as isotretinoin is likely to cause dryness of the skin and lips.
Eye disorders
Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy.
Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement
therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during
treatment.
Decreased night vision has also been reported and the onset in so me patients was sudden (see section 4.7).
Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal
of isotretinoin may be necessary.
Musculo-skeletal and connective tissue disorders
Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving
isotretinoin, particularly in those undertaking vigorous physical activity (see section 4.8).
Bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments
have occurred after several years of administration at very high doses for treating disorders of keratinisation. The
dose levels, duration of treatment and total cumulative dose in these patients generally far exceeded those
recommended for the treatment of acne.
Benign intracranial hypertension
Cases of benign intracranial hypertension have been reported, some of which involved concomitant use of
tetracyclines (see section 4.3 and section 4.5). Signs and sympto ms of benign intracranial hypertension include
headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial
hypertension should discontinue isotretinoin immediately.
Hepatobiliary disorders
Liver enzymes should be checked before treatment, 1 month after the start of treatment, and subsequently at 3
monthly intervals unless more frequent monitoring is clinically indicated. Transient and reversible increases in
liver transaminases have been reported. In many cases these changes have been within the normal range and
values have returned to baseline levels during treatment. However, in the event of persistent clinically relevant
elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.
Renal insufficiency
Renal insufficiency and renal failure do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin
can be given to patients with renal insufficiency. However, it is recommended that patients are started on a low
dose and titrated up to the maximu m tolerated dose (see section 4.2).
Lipid Metabolism
Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and
subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated. Elevated serum lipid
values usually return to normal on reduction of the dose or discontinuation of treatment and may also respond to
dietary measures.
Isotretinoin has been associated with an increase in plasma triglyceride levels. Isotretinoin should be
discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis
occur (see section 4.8). Levels in excess of 800 mg/dL or 9 mmol/L are sometimes associa ted with acute
pancreatitis, which may be fatal.
Gastrointestinal disorders
Isotretinoin has been associated with inflammatory bowel disease (including regional ileitis) in patients without a
prior history of intestinal disorders. Patients experiencing s evere (hemorrhagic) diarrhoea should discontinue
isotretinoin immediately.
Allergic reactions
Anaphylactic reactions have been rarely reported, in some cases after previous topical exposure to retinoids.
Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura
(bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic
reactions necessitate interruption of therapy and careful monitoring.
Fructose intolerance
Isotretinoin 5 mg capsules contain sorbitol. Patients with rare hereditary problems of fructose intolerance should
not take this medicine.
High Risk Patients
In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder underg oing treatment with
isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated
fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during isotretinoin
therapy.

4.5
Interaction with other medicinal products and other forms of interaction

Patients should not take vitamin A as concurrent medication due to the risk of developing hypervitaminosis A.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of
isotretinoin and tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided (see section
4.3 and section 4.4).
Concurrent administration of isotretinoin with topical keratolytic or exfoliative anti-acne agents should be
avoided as local irritation may increase (see section 4.4).

4.6
Fertility, Pregnancy and lactation

Pregnancy is an absolute contraindication to treatment with isotretinoin (see section 4.3). If pregnancy
does occur in spite of these precautions during treatment with isotretinoin or in the month following, there
is a great risk of very severe and serious malformation of the foetus.
The foetal malformations associated with exposure to isotretinoin include central nervous system abnormalities
(hydrocephalus, cerebellar malformation/abnormalit ies, microcephaly), facial dysmorphia, cleft palate, external
ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities
(microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot,
transposition of great vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities.
There is also an increased incidence of spontaneous abortion.
If pregnancy occurs in a woman treated with isotretinoin, treatment must be stopped and the patient should be
referred to a physician specialised or experienced in teratology for evaluation and advice.
Lactation:
Isotretinoin is highly lipophilic, therefore the passage of isotretinoin into human milk is very likely. Due to the
potential for adverse effects in the child exposed via mother’s milk, the use of isotretinoin is contraindicated in
nursing mothers.
4.7
Effects on ability to drive and use machines

Isotretinoin has minor or moderate influence on the ability to drive and use machines.
A number of cases of decreased night vision have occurred during isotretinoin therapy and in rare instances have
persisted after therapy (see section 4.4 and section 4.8). Because the onset in some patients was sudden, patients
should be advised of this potential problem and warned to be cautious when driving or operating machines.
Drowsiness, dizziness and visual disturbances have been reported very rarely. Patients should be warned that if
they experience these effects, they should not drive, operate machinery or take part in any other activities where
the symptoms could put either themselves or others at risk.
4.8
Undesirable effects
Some of the side effects associated with the use of isotretinoin are dose-related. The side effects are generally reversible after altering the dose or discontinuation of treatment, however some may persist after treatment has stopped. The following terminologies have been used in order to clas sify the occurrence of undesirable effects: Very common (1/10) Common (1/100 to <1/10) Uncommon (1/1,000 to <1/100) Rare (1/10,000 to <1/1,000) Very rare (<1/10,000), not known (cannot be estimated from the available data) The following symptoms are the most commonly reported undesirable effects with isotretinoin: dryness of the skin, dryness of the mucosa e.g. of the lips (cheilitis), the nasal mucosa (epistaxis), and the eyes (conjunctivitis). Gram positive (mucocutaneous) bacterial infection Blood and lymphatic system disorders: Very common Anaemia, red blood cell sedimentation rate increased, thrombocytopenia, thrombocytosis Allergic skin reaction, anaphylactic reactions, hypersensitivity Metabolism and nutrition disorders: Very rare Depression, depression aggravated, aggressive tendencies, anxiety, mood alterations Abnormal behaviour, psychotic disorder, suicidal ideation , suicide Benign intracranial hypertension, convulsions, drowsiness, dizziness Blepharitis, conjunctivitis, dry eye, eye irritation Blurred vision, cataract, colour blindness (colour vision deficiencies), contact lens intolerance, corneal opacity, decreased night vision, keratitis, papilloedema (as sign of benign intracranial hypertension), photophobia, visual disturbances Ear and labyrinth disorders: Very rare Vasculitis (for example Wegener's granulomatosis, allergic vasculitis) Respiratory, thoracic and mediastinal disorders: Common Epistaxis, nasal dryness, nasopharyngitis Bronchospasm (particularly in patients with asthma), hoarseness Gastrointestinal disorders: Very rare Colitis, ileitis, dry throat, gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, nausea, pancreatitis (see section 4.4) Hepatobiliary disorders: Very common Transaminase increased (see section 4.4) Sk in and subcutaneous tissue disorders: Very common Cheilitis, dermatitis, dry skin, localis ed exfoliation, pruritus, rash erythematous, skin fragility (risk of frictional trauma) Acne fulminans, acne aggravated (acne flare), erythema (facial), exanthema, hair disorders, hirsutism, nail dystrophy, paronychia, photosensitivity reaction, pyogenic granuloma, skin hyperpigmentation, sweating increased Erythema multiforme, Stevens -Johnson Syndrome, toxic epidermal necrolysis Musculo-sk eletal and connective tissue disorders: Very common Arthralgia, myalgia, back pain (particularly in children and adolescent patients) Arthritis, calcinosis (calcification of ligaments and tendons), epiphyses premature fusion, exostosis, (hyperostosis), reduced bone density, tendonitis , rhabdomyolysis Renal and urinary disorders: Very rare General disorders and administration site conditions: Very rare Granulation tissue (increased formation of), malaise Blood triglycerides increased, high density lipoprotein decreased Blood cholesterol increased, blood glucose increased, haematuria, proteinuria * cannot be estimated from the available data.
The incidence of the adverse events was calculated from pooled clinical trial data involving 824 patients and
from post-marketing data.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows
continued monitoring of the benefit/ris k balance of the medicinal product. Healthcare professionals are asked to
report any suspected adverse reaction via the national system listed in Appendix V.

4.9
Overdose

Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretin oin is low, signs of
hypervitaminosis A could appear in cases of accidental overdose. Manifestations of acute vitamin A toxicity
include severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Signs and symptoms of
accidental or deliberate overdosage with isotretinoin would probably be similar. These symptoms would be
expected to be reversible and to subside without the need for treatment.

5.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties

Pharmacotherapeutic group: Anti-acne preparations for systemic use, Retinoids for treatment of acne
ATC code: D10BA01
Mechanism of action
Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of isotretinoin
has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical
picture of severe acne is associated with suppression of sebaceous gland activity and a histologically
demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of
isotretinoin has been established.
Clinical efficacy
Hypercornification of the epithelial lining of the pilosebaceous unit leads to shedding of corneocytes into the
duct and blockage by keratin and excess sebum. This is followed by formation of a comedone and, eventually,
inflammatory lesions. Isotretinoin inhibits proliferation of sebocytes and appears to act in acne by re -setting the
orderly program of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that
reduced sebum production inhibits bacterial colonisation of the duct.

5.2
Pharmacokinetic properties

Absorption
The absorption of isotretinoin from the gastro-intestinal tract is variable and dose-linear over the therapeutic
range. The absolute bioavailability of isotretinoin has not been determined, since the compound is not available
as an intravenous preparation for human use, but extrapolation from dog studies would suggest a fairly low and
variable systemic bioavailability. When isotretinoin is taken with food, the bioavailability is doubled relative to
fasting conditions.
Distribution
Isotretinoin is extensively bound to plasma proteins, mainly albumin (99.9 %). The volume of distribution of
isotretinoin in man has not been determined since isotretinoin is not available as an intravenous preparation for
human use. In humans little information is available on the distribution of isotretinoin into tissue. Concentrations
of isotretinoin in the epidermis are only half of those in serum. Plasma concentrations of isotretinoin are about
1.7 times those of whole blood due to poor penetration of isotretinoin into red blood cells.
Biotransformation
After oral administration of isotretinoin, three major metabolites have been iden tified in plasma: 4-oxo-
isotretinoin, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological
activity in several in vitro tests. 4-oxo-isotretinoin has been shown in a clinical study to be a significant
contributor to the activity of isotretinoin (reduction in sebum excretion rate despite no effect on plasma levels of
isotretinoin and tretinoin). Other minor metabolites include glucuronide conjugates. The major metabolite is 4-
oxo-isotretinoin with plasma concentrations at steady state, that are 2.5 times higher than those of the parent
compound.
Isotretinoin and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism
of tretinoin is therefore linked with that of isotretinoin. It has been estimated that 20-30 % of an isotretinoin dose
is metabolised by isomerisation.
Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in man. In vitro
metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of isotretinoin
to 4-oxo-isotretinoin and tretinoin. No single isoform appears to have a predominant role. Isotretinoin and its
metabolites do not significantly affect CYP activity.
Elimination
After oral administration of radiolabelled isotretinoin approximately equal fractions of the dose were recovered
in urine and faeces. Following oral administration of isotretinoin, the terminal elimination half-life of unchanged
drug in patients with acne has a mean value of 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin
is longer, with a mean value of 29 hours.
Isotretinoin is a physiological retinoid and endogenous retinoid concentrations are reached within approximately
two weeks following the end of isotretinoin therapy.
Pharmacokinetics in special populations
Since isotretinoin is contraindicated in patients with hepatic impairment, limited information on the kinetics of
isotretinoin is available in this patient population. Renal failure do es not significantly reduce the plasma
clearance of isotretinoin or 4-oxo-isotretinoin.
Preclinical safety data

Acute toxicity
The acute oral toxicity of isotretinoin was determined in various animal species. LD50 is approximately 2000
mg/kg in rabbits, approximately 3000 mg/kg in mice, and over 4000 mg/kg in rats.
Chronic toxicity
A long-term study in rats over 2 years (isotretinoin dosage 2, 8 and 32 mg/kg/d) produced evidence of partial
hair loss and elevated plasma triglycerides in the higher do se groups. The side effect spectrum of isotretinoin in
the rodent thus closely resembles that of vitamin A, but does not include the massive tissue and organ
calcifications observed with vitamin A in the rat. The liver cell changes observed with vitamin A did not occur
with isotretinoin.
All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of
isotretinoin. Even experimental animals in a poor general state had largely recovered within 1–2 weeks.
Teratogenicity
Like other vitamin A derivatives, isotretinoin has been shown in animal experiments to be teratogenic and
embryotoxic.
Due to the teratogenic potential of isotretinoin there are therapeutic consequences for the administration to
women of a childbearing age (see section 4.3, section 4.4, and section 4.6).
Fertility
Isotretinoin, in therapeutic dosages, does not affect the number, motility and morphology of sperm and does not
jeopardise the formation and development of the embryo on the part of the men taking isotretinoin.
Mutagenicity
Isotretinoin has not been shown to be mutagenic in in vitro or in vivo animal tests.
PHARMACEUTICAL PARTICULARS
List of excipients
Capsule filling: Soya-bean oil, refined all-rac-α-Tocopherol Disodium edetate Butylhydroxyanisole (E 320) Soya-bean oil, partially hydrogenated Hydrogenated vegetable oil Beeswax, yellow Capsule shell: Gelatin Glycerol Sorbitol, liquid (non-crystallising) (E 420) Purified water Titanium dioxide (E 171) Incompati bilities

Not applicable.

6.3
Shelf life

2 years.
6.4
Special precautions for storage
Do not store above 30°C. Store in the original package. Nature and contents of container

AL/PVC/PVDC blisters.
10, 15, 20, 30, 50 and 60 capsules
Not all pack sizes may be marketed.

6.6
Special precautions for disposal
Return any unused Isotretinon 5 mg capsules to the Pharmacist. MARKETING AUTHORISATION HOLDER
[To be completed nationally]

8.
MARKETING AUTHORISATION NUMBER(S)


9.
DATE OF FIRST AUTHORISATION/RENEW AL OF THE AUTHORISATION
DATE OF REVISION OF THE TEXT

Source: http://www.cts-mrp.eu/download/AT_H_0164_001_FinalSPC.pdf