Components:
Isotretinoin
Isotretinoin
Method of action:
Anesthetic, Anti-Inflammatory, Antiseborrheic, Dermatoprotective, Keratolytic, Regenerative
Anesthetic, Anti-Inflammatory, Antiseborrheic, Dermatoprotective, Keratolytic, Regenerative
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Name of the medicinal product

13-cys-Retinoic acid

Qualitative and quantitative composition

Isotretinoin

Pharmaceutical form

Substance-powder

Therapeutic indications

The information provided in Therapeutic indications of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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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 antibacterials and topical therapy.

Dosage (Posology) and method of administration

The information provided in Dosage (Posology) and method of administration of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Posology

13-cys-Retinoic acid 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 understanding of the risks of 13-cys-Retinoic acid therapy and monitoring requirements.

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

Adults including adolescents and the elderly:

13-cys-Retinoic acid therapy should be started at a dose of 0.5 mg/kg daily. The therapeutic response to 13-cys-Retinoic acid 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 13-cys-Retinoic acid 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 renal impairment

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 maximum tolerated dose .

Paediatric population

13-cys-Retinoic acid 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 maximum possible efficacy in these patients the dose should normally be continued at the highest tolerated dose.

Method of administration

Oral use.

Contraindications

The information provided in Contraindications of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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13-cys-Retinoic acid is contraindicated in women who are pregnant or breast-feeding .

13-cys-Retinoic acid is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met .

13-cys-Retinoic acid is also contraindicated in patients

With hepatic insufficiency

With excessively elevated blood lipid values

With hypervitaminosis A

With hypersensitivity to 13-cys-Retinoic acid or to any of the excipients

Receiving concomitant treatment with tetracyclines

Allergic to peanut or soya oil as 13-cys-Retinoic acid contains soya-bean oil

Special warnings and precautions for use

The information provided in Special warnings and precautions for use of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Pregnancy Prevention Programme

This medicinal product is TERATOGENIC

13-cys-Retinoic acid 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 .

She understands the teratogenic risk.

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 amenorrhoea she must follow all of the advice on effective 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 use of 13-cys-Retinoic acid.

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 barrier 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 contraception including a barrier method. Contraception should be continued for at least 1 month after stopping treatment with 13-cys-Retinoic acid, even in patients with amenorrhoea.

Pregnancy testing

According to local practice medically supervised pregnancy tests with 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 that 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 13-cys-Retinoic acid 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 13-cys-Retinoic acid.

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 amenorrhoea). 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 13-cys-Retinoic acid 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 13-cys-Retinoic acid should occur on the same day. Dispensing of 13-cys-Retinoic acid should occur within a maximum 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 13-cys-Retinoic acid, is not of a sufficient magnitude to be associated with the teratogenic effects of 13-cys-Retinoic acid.

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 13-cys-Retinoic acid because of the potential risk to the fetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding fetal exposure to 13-cys-Retinoic acid the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of 13-cys-Retinoic acid, 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 physician to all patients, both male and female.

Psychiatric disorders

Depression including aggravation of pre-existing depression, anxiety, aggressive tendencies, mood alterations, psychotic symptoms and, very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with 13-cys-Retinoic acid . 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 13-cys-Retinoic acid may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Skin and subcutaneous tissues 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.

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 13-cys-Retinoic acid for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on 13-cys-Retinoic acid for at least a period of 6 months after treatment because of the risk of epidermal stripping.

Concurrent administration of 13-cys-Retinoic acid with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase .

Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as 13-cys-Retinoic acid is likely to cause dryness of the skin and lips.

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 13-cys-Retinoic acid use. As these events may be difficult to distinguish from other skin reactions that may occur , patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, 13-cys-Retinoic acid treatment should be discontinued.

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.

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 some patients was sudden . Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal of 13-cys-Retinoic acid may be necessary.

Musculo-skeletal and connective tissue disorders

Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving 13-cys-Retinoic acid, particularly in those undertaking vigorous physical activity . In some cases, this may progress to potentially life threatening rhabdomyolysis.

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 . Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial hypertension should discontinue 13-cys-Retinoic acid 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 13-cys-Retinoic acid. Therefore, 13-cys-Retinoic acid 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 maximum tolerated dose .

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.

13-cys-Retinoic acid has been associated with an increase in plasma triglyceride levels. 13-cys-Retinoic acid should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur . Levels in excess of 800 mg/dL or 9 mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders

13-cys-Retinoic acid has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (haemorrhagic) diarrhoea should discontinue 13-cys-Retinoic acid immediately.

High risk patients

In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with 13-cys-Retinoic acid, 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 13-cys-Retinoic acid therapy.

Effects on ability to drive and use machines

The information provided in Effects on ability to drive and use machines of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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13-cys-Retinoic acid could potentially have an influence on the ability to drive and use machines.

A number of cases of decreased night vision have occurred during 13-cys-Retinoic acid therapy and in rare instances have persisted after therapy . 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.

Undesirable effects

The information provided in Undesirable effects of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Summary of safety profile

Some of the side effects associated with the use of 13-cys-Retinoic acid 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 symptoms are the most commonly reported undesirable effects with 13-cys-Retinoic acid: dryness of the mucosae e.g. of the lips (cheilitis), the nasal mucosa (epistaxis), and the eyes (conjunctivitis), dryness of the skin.

Tabulated list of adverse reactions

The incidence of the adverse reactions calculated from pooled clinical trial data involving 824 patients and from postmarketing data are presented in the table below. The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as 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 to <1/1,000) and not known (cannot be estimated from the available data). Within each frequency grouping and SOC, adverse reactions are presented in order of decreasing seriousness.

Table 1 Tabulated list of adverse reactions in patients treated with 13-cys-Retinoic acid

System Organ Class

Very Common

Common

Rare

Very Rare

Not Known

Infections and infestations:

Gram positive (mucocutaneous) bacterial infection

Blood and lymphatic system disorders:

Anaemia, Red blood cell sedimentation rate increased, Thrombocytopenia, Thrombocytosis

Neutropenia

Lymphadenopathy

Immune system disorders:

Allergic skin reaction, Anaphylactic reactions, Hypersensitivity

Metabolism and nutrition disorders:

Diabetes mellitus, Hyperuricaemia

Psychiatric disorders:

Depression including aggravation of pre-existing depression Aggressive tendencies, Anxiety, Mood Alterations

Abnormal behaviour, Psychotic disorder, Suicidal ideation, Suicide attempt, Suicide

Nervous system disorders:

Headache

Benign intracranial hypertension Convulsions, Drowsiness, Dizziness

Eye disorders:

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:

Hearing impaired

Vascular disorders:

Vasculitis (for example Wegener's granulomatosis, allergic vasculitis)

Respiratory, thoracic and mediastinal disorders:

Epistaxis, Nasal dryness, Nasopharyngitis

Bronchospasm (particularly in patients with asthma), Hoarseness

Gastrointestinal disorders:

Colitis, Ileitis, Dry throat, Gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, Nausea, Pancreatitis

Hepatobiliary disorders:

Transaminase increased

Hepatitis

Skin and subcutaneous tissues disorders:

Cheilitis, Dermatitis, Dry skin, Localised exfoliation, Pruritus, Rash erythematous, Skin fragility (and risk of frictional trauma)

Alopecia

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.

Musculoskeletal and connective tissue disorders:

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:

Glomerulonephritis

Reproductive system and breast disorders

Sexual dysfunction including erectile dysfunction and decreased libido

General disorders and administration site conditions:

Granulation tissue (increased formation of), Malaise

Investigations:

Blood triglycerides increased, High density lipoprotein decreased

Blood cholesterol increased, Blood glucose increased, Haematuria, Proteinuria

Blood creatine phosphokinase increased

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Overdose

The information provided in Overdose of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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13-cys-Retinoic acid is a derivative of vitamin A. Although the acute toxicity of 13-cys-Retinoic acid 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 13-cys-Retinoic acid would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment.

Pharmacodynamic properties

The information provided in Pharmacodynamic properties of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Pharmacotherapeutic group: Retinoid for the treatment of acne, ATC code: D10BA01

Mechanism of action

13-cys-Retinoic acid is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of 13-cys-Retinoic acid 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 13-cys-Retinoic acid has been established.

Clinical efficacy and safety

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. 13-cys-Retinoic acid inhibits proliferation of sebocytes and appears to act in acne by re-setting the orderly programme of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduced sebum production inhibits bacterial colonisation of the duct.

Pharmacokinetic properties

The information provided in Pharmacokinetic properties of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Absorption

The absorption of 13-cys-Retinoic acid from the gastro-intestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of 13-cys-Retinoic acid 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 13-cys-Retinoic acid is taken with food, the bioavailability is doubled relative to fasting conditions.

Distribution

13-cys-Retinoic acid is extensively bound to plasma proteins, mainly albumin (99.9%). The volume of distribution of 13-cys-Retinoic acid in man has not been determined since 13-cys-Retinoic acid is not available as an intravenous preparation for human use. In humans little information is available on the distribution of 13-cys-Retinoic acid into tissue. Concentrations of 13-cys-Retinoic acid in the epidermis are only half of those in serum. Plasma concentrations of 13-cys-Retinoic acid are about 1.7 times those of whole blood due to poor penetration of 13-cys-Retinoic acid into red blood cells.

Biotransformation

After oral administration of 13-cys-Retinoic acid, three major metabolites have been identified in plasma: 4-oxo-13-cys-Retinoic acid, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological activity in several in vitro tests. 4-oxo-13-cys-Retinoic acid has been shown in a clinical study to be a significant contributor to the activity of 13-cys-Retinoic acid (reduction in sebum excretion rate despite no effect on plasma levels of 13-cys-Retinoic acid and tretinoin). Other minor metabolites include glucuronide conjugates. The major metabolite is 4-oxo-13-cys-Retinoic acid with plasma concentrations at steady state, that are 2.5 times higher than those of the parent compound.

13-cys-Retinoic acid and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism of tretinoin is therefore linked with that of 13-cys-Retinoic acid. It has been estimated that 20-30% of an 13-cys-Retinoic acid dose is metabolised by isomerisation.

Enterohepatic circulation may play a significant role in the pharmacokinetics of 13-cys-Retinoic acid in man. In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of 13-cys-Retinoic acid to 4-oxo-13-cys-Retinoic acid and tretinoin. No single isoform appears to have a predominant role. 13-cys-Retinoic acid and its metabolites do not significantly affect CYP activity.

Elimination

After oral administration of radiolabelled 13-cys-Retinoic acid approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of 13-cys-Retinoic acid, 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-13-cys-Retinoic acid is longer, with a mean value of 29 hours.

13-cys-Retinoic acid is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of 13-cys-Retinoic acid therapy.

Hepatic impairment

Since 13-cys-Retinoic acid is contraindicated in patients with hepatic impairment, limited information on the kinetics of 13-cys-Retinoic acid is available in this patient population.

Renal impairment

Renal failure does not significantly reduce the plasma clearance of 13-cys-Retinoic acid or 4-oxo-13-cys-Retinoic acid.

Pharmacotherapeutic group

The information provided in Pharmacotherapeutic group of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Retinoid for the treatment of acne, ATC code: D10BA01

Preclinical safety data

The information provided in Preclinical safety data of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Acute toxicity

The acute oral toxicity of 13-cys-Retinoic acid 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 (13-cys-Retinoic acid dosage 2, 8 and 32 mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides in the higher dose groups. The side effect spectrum of 13-cys-Retinoic acid 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 13-cys-Retinoic acid.

All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of 13-cys-Retinoic acid. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.

Teratogenicity

Like other vitamin A derivatives, 13-cys-Retinoic acid has been shown in animal experiments to be teratogenic and embryotoxic.

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Mutagenicity

13-cys-Retinoic acid has not been shown to be mutagenic nor carcinogenic in in vitro or in vivo animal tests respectively.

Incompatibilities

The information provided in Incompatibilities of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Not applicable.

Special precautions for disposal and other handling

The information provided in Special precautions for disposal and other handling of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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No special instructions.

Name of the medicinal product
13-cys-Retinoic acid
Qualitative and quantitative composition
Isotretinoin
Pharmaceutical form
Substance-powder
Therapeutic indications
The information provided in Therapeutic indications of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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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 antibacterials and topical therapy.

Dosage (Posology) and method of administration
The information provided in Dosage (Posology) and method of administration of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Posology

13-cys-Retinoic acid 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 understanding of the risks of 13-cys-Retinoic acid therapy and monitoring requirements.

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

Adults including adolescents and the elderly:

13-cys-Retinoic acid therapy should be started at a dose of 0.5 mg/kg daily. The therapeutic response to 13-cys-Retinoic acid 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 13-cys-Retinoic acid 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 renal impairment

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 maximum tolerated dose .

Paediatric population

13-cys-Retinoic acid 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 maximum possible efficacy in these patients the dose should normally be continued at the highest tolerated dose.

Method of administration

Oral use.

Contraindications
The information provided in Contraindications of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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13-cys-Retinoic acid is contraindicated in women who are pregnant or breast-feeding .

13-cys-Retinoic acid is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met .

13-cys-Retinoic acid is also contraindicated in patients

With hepatic insufficiency

With excessively elevated blood lipid values

With hypervitaminosis A

With hypersensitivity to 13-cys-Retinoic acid or to any of the excipients

Receiving concomitant treatment with tetracyclines

Allergic to peanut or soya oil as 13-cys-Retinoic acid contains soya-bean oil

Special warnings and precautions for use
The information provided in Special warnings and precautions for use of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Pregnancy Prevention Programme

This medicinal product is TERATOGENIC

13-cys-Retinoic acid 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 .

She understands the teratogenic risk.

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 amenorrhoea she must follow all of the advice on effective 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 use of 13-cys-Retinoic acid.

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 barrier 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 contraception including a barrier method. Contraception should be continued for at least 1 month after stopping treatment with 13-cys-Retinoic acid, even in patients with amenorrhoea.

Pregnancy testing

According to local practice medically supervised pregnancy tests with 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 that 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 13-cys-Retinoic acid 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 13-cys-Retinoic acid.

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 amenorrhoea). 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 13-cys-Retinoic acid 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 13-cys-Retinoic acid should occur on the same day. Dispensing of 13-cys-Retinoic acid should occur within a maximum 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 13-cys-Retinoic acid, is not of a sufficient magnitude to be associated with the teratogenic effects of 13-cys-Retinoic acid.

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 13-cys-Retinoic acid because of the potential risk to the fetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding fetal exposure to 13-cys-Retinoic acid the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of 13-cys-Retinoic acid, 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 physician to all patients, both male and female.

Psychiatric disorders

Depression including aggravation of pre-existing depression, anxiety, aggressive tendencies, mood alterations, psychotic symptoms and, very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with 13-cys-Retinoic acid . 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 13-cys-Retinoic acid may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Skin and subcutaneous tissues 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.

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 13-cys-Retinoic acid for a period of 5-6 months after the end of the treatment because of the risk of hypertrophic scarring in atypical areas and more rarely post inflammatory hyper or hypopigmentation in treated areas. Wax depilation should be avoided in patients on 13-cys-Retinoic acid for at least a period of 6 months after treatment because of the risk of epidermal stripping.

Concurrent administration of 13-cys-Retinoic acid with topical keratolytic or exfoliative anti-acne agents should be avoided as local irritation may increase .

Patients should be advised to use a skin moisturising ointment or cream and a lip balm from the start of treatment as 13-cys-Retinoic acid is likely to cause dryness of the skin and lips.

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 13-cys-Retinoic acid use. As these events may be difficult to distinguish from other skin reactions that may occur , patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If a severe skin reaction is suspected, 13-cys-Retinoic acid treatment should be discontinued.

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.

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 some patients was sudden . Patients experiencing visual difficulties should be referred for an expert ophthalmological opinion. Withdrawal of 13-cys-Retinoic acid may be necessary.

Musculo-skeletal and connective tissue disorders

Myalgia, arthralgia and increased serum creatine phosphokinase values have been reported in patients receiving 13-cys-Retinoic acid, particularly in those undertaking vigorous physical activity . In some cases, this may progress to potentially life threatening rhabdomyolysis.

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 . Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop benign intracranial hypertension should discontinue 13-cys-Retinoic acid 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 13-cys-Retinoic acid. Therefore, 13-cys-Retinoic acid 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 maximum tolerated dose .

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.

13-cys-Retinoic acid has been associated with an increase in plasma triglyceride levels. 13-cys-Retinoic acid should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur . Levels in excess of 800 mg/dL or 9 mmol/L are sometimes associated with acute pancreatitis, which may be fatal.

Gastrointestinal disorders

13-cys-Retinoic acid has been associated with inflammatory bowel disease (including regional ileitis) in patients without a prior history of intestinal disorders. Patients experiencing severe (haemorrhagic) diarrhoea should discontinue 13-cys-Retinoic acid immediately.

High risk patients

In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with 13-cys-Retinoic acid, 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 13-cys-Retinoic acid therapy.

Effects on ability to drive and use machines
The information provided in Effects on ability to drive and use machines of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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13-cys-Retinoic acid could potentially have an influence on the ability to drive and use machines.

A number of cases of decreased night vision have occurred during 13-cys-Retinoic acid therapy and in rare instances have persisted after therapy . 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.

Undesirable effects
The information provided in Undesirable effects of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Summary of safety profile

Some of the side effects associated with the use of 13-cys-Retinoic acid 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 symptoms are the most commonly reported undesirable effects with 13-cys-Retinoic acid: dryness of the mucosae e.g. of the lips (cheilitis), the nasal mucosa (epistaxis), and the eyes (conjunctivitis), dryness of the skin.

Tabulated list of adverse reactions

The incidence of the adverse reactions calculated from pooled clinical trial data involving 824 patients and from postmarketing data are presented in the table below. The adverse reactions are listed below by MedDRA system organ class (SOC) and categories of frequency. Frequency categories are defined as 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 to <1/1,000) and not known (cannot be estimated from the available data). Within each frequency grouping and SOC, adverse reactions are presented in order of decreasing seriousness.

Table 1 Tabulated list of adverse reactions in patients treated with 13-cys-Retinoic acid

System Organ Class

Very Common

Common

Rare

Very Rare

Not Known

Infections and infestations:

Gram positive (mucocutaneous) bacterial infection

Blood and lymphatic system disorders:

Anaemia, Red blood cell sedimentation rate increased, Thrombocytopenia, Thrombocytosis

Neutropenia

Lymphadenopathy

Immune system disorders:

Allergic skin reaction, Anaphylactic reactions, Hypersensitivity

Metabolism and nutrition disorders:

Diabetes mellitus, Hyperuricaemia

Psychiatric disorders:

Depression including aggravation of pre-existing depression Aggressive tendencies, Anxiety, Mood Alterations

Abnormal behaviour, Psychotic disorder, Suicidal ideation, Suicide attempt, Suicide

Nervous system disorders:

Headache

Benign intracranial hypertension Convulsions, Drowsiness, Dizziness

Eye disorders:

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:

Hearing impaired

Vascular disorders:

Vasculitis (for example Wegener's granulomatosis, allergic vasculitis)

Respiratory, thoracic and mediastinal disorders:

Epistaxis, Nasal dryness, Nasopharyngitis

Bronchospasm (particularly in patients with asthma), Hoarseness

Gastrointestinal disorders:

Colitis, Ileitis, Dry throat, Gastrointestinal haemorrhage, haemorrhagic diarrhoea and inflammatory bowel disease, Nausea, Pancreatitis

Hepatobiliary disorders:

Transaminase increased

Hepatitis

Skin and subcutaneous tissues disorders:

Cheilitis, Dermatitis, Dry skin, Localised exfoliation, Pruritus, Rash erythematous, Skin fragility (and risk of frictional trauma)

Alopecia

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.

Musculoskeletal and connective tissue disorders:

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:

Glomerulonephritis

Reproductive system and breast disorders

Sexual dysfunction including erectile dysfunction and decreased libido

General disorders and administration site conditions:

Granulation tissue (increased formation of), Malaise

Investigations:

Blood triglycerides increased, High density lipoprotein decreased

Blood cholesterol increased, Blood glucose increased, Haematuria, Proteinuria

Blood creatine phosphokinase increased

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Overdose
The information provided in Overdose of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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13-cys-Retinoic acid is a derivative of vitamin A. Although the acute toxicity of 13-cys-Retinoic acid 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 13-cys-Retinoic acid would probably be similar. These symptoms would be expected to be reversible and to subside without the need for treatment.

Pharmacodynamic properties
The information provided in Pharmacodynamic properties of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Pharmacotherapeutic group: Retinoid for the treatment of acne, ATC code: D10BA01

Mechanism of action

13-cys-Retinoic acid is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of 13-cys-Retinoic acid 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 13-cys-Retinoic acid has been established.

Clinical efficacy and safety

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. 13-cys-Retinoic acid inhibits proliferation of sebocytes and appears to act in acne by re-setting the orderly programme of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduced sebum production inhibits bacterial colonisation of the duct.

Pharmacokinetic properties
The information provided in Pharmacokinetic properties of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Absorption

The absorption of 13-cys-Retinoic acid from the gastro-intestinal tract is variable and dose-linear over the therapeutic range. The absolute bioavailability of 13-cys-Retinoic acid 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 13-cys-Retinoic acid is taken with food, the bioavailability is doubled relative to fasting conditions.

Distribution

13-cys-Retinoic acid is extensively bound to plasma proteins, mainly albumin (99.9%). The volume of distribution of 13-cys-Retinoic acid in man has not been determined since 13-cys-Retinoic acid is not available as an intravenous preparation for human use. In humans little information is available on the distribution of 13-cys-Retinoic acid into tissue. Concentrations of 13-cys-Retinoic acid in the epidermis are only half of those in serum. Plasma concentrations of 13-cys-Retinoic acid are about 1.7 times those of whole blood due to poor penetration of 13-cys-Retinoic acid into red blood cells.

Biotransformation

After oral administration of 13-cys-Retinoic acid, three major metabolites have been identified in plasma: 4-oxo-13-cys-Retinoic acid, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites have shown biological activity in several in vitro tests. 4-oxo-13-cys-Retinoic acid has been shown in a clinical study to be a significant contributor to the activity of 13-cys-Retinoic acid (reduction in sebum excretion rate despite no effect on plasma levels of 13-cys-Retinoic acid and tretinoin). Other minor metabolites include glucuronide conjugates. The major metabolite is 4-oxo-13-cys-Retinoic acid with plasma concentrations at steady state, that are 2.5 times higher than those of the parent compound.

13-cys-Retinoic acid and tretinoin (all-trans retinoic acid) are reversibly metabolised (interconverted), and the metabolism of tretinoin is therefore linked with that of 13-cys-Retinoic acid. It has been estimated that 20-30% of an 13-cys-Retinoic acid dose is metabolised by isomerisation.

Enterohepatic circulation may play a significant role in the pharmacokinetics of 13-cys-Retinoic acid in man. In vitro metabolism studies have demonstrated that several CYP enzymes are involved in the metabolism of 13-cys-Retinoic acid to 4-oxo-13-cys-Retinoic acid and tretinoin. No single isoform appears to have a predominant role. 13-cys-Retinoic acid and its metabolites do not significantly affect CYP activity.

Elimination

After oral administration of radiolabelled 13-cys-Retinoic acid approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of 13-cys-Retinoic acid, 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-13-cys-Retinoic acid is longer, with a mean value of 29 hours.

13-cys-Retinoic acid is a physiological retinoid and endogenous retinoid concentrations are reached within approximately two weeks following the end of 13-cys-Retinoic acid therapy.

Hepatic impairment

Since 13-cys-Retinoic acid is contraindicated in patients with hepatic impairment, limited information on the kinetics of 13-cys-Retinoic acid is available in this patient population.

Renal impairment

Renal failure does not significantly reduce the plasma clearance of 13-cys-Retinoic acid or 4-oxo-13-cys-Retinoic acid.

Pharmacotherapeutic group
The information provided in Pharmacotherapeutic group of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Retinoid for the treatment of acne, ATC code: D10BA01
Preclinical safety data
The information provided in Preclinical safety data of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Acute toxicity

The acute oral toxicity of 13-cys-Retinoic acid 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 (13-cys-Retinoic acid dosage 2, 8 and 32 mg/kg/d) produced evidence of partial hair loss and elevated plasma triglycerides in the higher dose groups. The side effect spectrum of 13-cys-Retinoic acid 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 13-cys-Retinoic acid.

All observed side effects of hypervitaminosis A syndrome were spontaneously reversible after withdrawal of 13-cys-Retinoic acid. Even experimental animals in a poor general state had largely recovered within 1-2 weeks.

Teratogenicity

Like other vitamin A derivatives, 13-cys-Retinoic acid has been shown in animal experiments to be teratogenic and embryotoxic.

<4 ).

Mutagenicity

13-cys-Retinoic acid has not been shown to be mutagenic nor carcinogenic in in vitro or in vivo animal tests respectively.

Incompatibilities
The information provided in Incompatibilities of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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Not applicable.

Special precautions for disposal and other handling
The information provided in Special precautions for disposal and other handling of 13-cys-Retinoic acid is based on data of another medicine with exactly the same composition as the 13-cys-Retinoic acid of the medicine (Isotretinoin). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug 13-cys-Retinoic acid directly from the package or from the pharmacist at the pharmacy.
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No special instructions.

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