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Isotretinoin

Isotretinoin acnetrait is a medicine in the form of a soft capsule (30) based on Isotretinoin (40 mg).

Indications: why take Isotretinoin?

Indications for use

  • Severe acne

Therapeutic indications

Severe acnes (such as lumpy acne, acne conglobata, or acne that may lead to permanent scarring) resistant to appropriate cures of conventional treatment including systemic antibiotics and topical treatment

Contraindications: why not take Isotretinoin?

Isotretinoin is contraindicated in pregnant or breast-feeding women (see section Fertility, pregnancy and breast-feeding ).

Isotretinoin is contraindicated in women of childbearing age unless all the conditions of the “Pregnancy Prevention Program” are met (see section 4.4 ).

Isotretinoin is also contraindicated in:

Hypersensitivity to the active substance or to any of the excipients listed in the Composition section ;

· Allergy to peanuts or soya because ISOTRETINOINE ACNETRAIT 40 mg, soft capsule contains soybean oil and partially hydrogenated soybean oil;

· Hepatic insufficiency ;

Hyperlipidemia;

Hypervitaminosis A;

Combination with tetracyclines (see section Interactions with other medicinal products and other forms of interactions );

Concomitant intake of vitamin A (see section Interactions with other medicinal products and other forms of interactions );

Concomitant intake of other retinoids (acitretin, alitretinoin) (see section Interactions with other medicinal products and other forms of interactions ).

Posology and method of administration

Dosage

The initial prescription of ISOTRETINOINE ACNETRAIT 40 mg, soft capsule is reserved for specialists in dermatology. The prescription can be renewed by any doctor.

Isotretinoin should only be prescribed by or under the supervision of physicians who have experience in the use of systemic retinoids in the treatment of severe acne and who are fully aware of the risks of isotretinoin and the monitoring of it. ‘it imposes.

The capsules should be swallowed during meals, once or twice a day.

Adolescents, adults and the elderly

Treatment with isotretinoin should be started at a dosage of 0.5 mg / kg / day.

The therapeutic response to isotretinoin and some of the side effects are dose dependent and vary from patient to patient. This requires individual dose adjustment during treatment. For most patients, the dose is between 0.5 and 1 mg / kg / day.

The rates of prolonged remission and relapse after a course of isotretinoin depend more on the total cumulative dose than on the duration of treatment or the daily dosage. Continuation of treatment beyond a cumulative dose of the order of 120 to 150 mg / kg has been shown to result in no significant additional benefit. The duration of treatment depends on the individual daily dose. A course of treatment lasting 16 to 24 weeks is usually sufficient to achieve remission.

In the majority of patients, a complete cure of acne is obtained after a single cure. In the event of a confirmed relapse, a new course of isotretinoin may be considered with the same daily dosage and the same cumulative therapeutic dose. As improvement of acne can continue for up to 8 weeks after stopping treatment, a new cure before the end of this period should not be considered.

Patients with severe renal impairment

In patients with severe renal impairment, treatment should be started at a lower dose (eg 10 mg / day). The dosage will then be increased gradually, up to 1 mg / kg / day, or up to the maximum dose tolerated by the patient (see section 4.4 ).

Pediatric population

Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in children under 12 years of age.

Intolerant patients

In patients with severe intolerance to the recommended dose, treatment may be continued at a lower dose, thus exposing the patient to a longer duration of treatment and an increased risk of relapse. In order to ensure the best possible efficacy in these patients, treatment should normally be continued at the maximum tolerated dose.

Soft capsule.

Warnings and precautions for use Isotretinoin

Teratogenic effects:

ISOTRETINOINE ACNETRAIT 40 mg, soft capsule is a potent teratogenic drug in humans causing a high incidence of severe and potentially fatal congenital anomalies in the unborn child.

ISOTRETINOINE ACNETRAIT 40 mg, soft capsule is strictly contraindicated in:

· pregnant women ;

· Women of childbearing age unless all the conditions of the Pregnancy Prevention Program are met.

Pregnancy Prevention Program

This drug is TERATOGENIC

Isotretinoin is contraindicated in women of childbearing potential, unless all the conditions of the Pregnancy Prevention Program are met:

The patient presents with severe acne (such as nodular acne, acne conglobata or acne liable to induce permanent scars) resistant to appropriate cures of conventional treatment comprising systemic antibiotics and topical treatment (see section Therapeutic indications “Therapeutic indications” );

The risk of pregnancy occurring should be assessed for all patients;

· The patient understands the teratogenic risk;

· She understands the need for rigorous follow-up each month;

She understands and accepts the need for effective contraception, without interruption, from 1 month before the start of treatment, throughout the duration of treatment and for 1 additional month after the end of treatment. The use of at least one highly effective method of contraception (the effectiveness of which is not user dependent), or two complementary contraceptive methods (if their effectiveness depends on the user), is necessary. ;

· When choosing the method of contraception, individual situations must be considered on a case-by-case basis, involving the patient in the discussion to ensure her commitment and compliance with the methods chosen;

· Even in the event of amenorrhea, she must follow the recommendations for effective contraception;

· She must be informed and understood the potential consequences of pregnancy and the need to consult a doctor quickly if there is a risk of pregnancy or if she thinks she is pregnant;

She understands and accepts the need for regular pregnancy tests: before, if possible each month during, and 1 month after stopping treatment;

· She acknowledges having understood the risks and necessary precautions associated with the use of isotretinoin.

These conditions also apply to women who are not currently sexually active, unless the prescriber considers that there are compelling reasons that the risk of pregnancy is zero.

The prescriber must ensure that:

· The patient complies with the pregnancy prevention conditions described above and is able to understand them.

· The patient has become aware of the conditions mentioned above;

The patient understands that she must correctly and continuously use one highly effective method of contraception (the effectiveness of which does not depend on the user), or two complementary methods of contraception (if their effectiveness depends on the user / eur) and that this is necessary for at least 1 month before the start of treatment and that effective contraception should be provided for the entire duration of treatment and for at least 1 month after stopping treatment.

Negative results have been obtained in pregnancy tests carried out before, during treatment and 1 month after the end of treatment. The dates and results of pregnancy tests should be traced.

In the event of pregnancy in a woman treated with isotretinoin, treatment should be discontinued and the patient should be referred to a physician specialized or experienced in teratology for evaluation and advice.

Even if pregnancy occurs after stopping treatment, there is still a risk of severe and serious malformation of the fetus. The risk persists until the drug has been completely eliminated, that is, 1 month after the end of treatment.

Contraception

Patients should be provided with comprehensive information on preventing pregnancy and should be able to benefit from the advice of a specialist doctor if they are not using an effective method of contraception. If the prescriber is unable to provide this type of information, the patient should be referred to another health care professional more able to do so.

At a minimum, women of childbearing potential should use at least one highly effective method of contraception (the effectiveness of which is not user dependent), or two complementary contraceptive methods (if their effectiveness is user dependent. ). A method of contraception should be used for at least 1 month before the start of treatment, for the duration of treatment and for at least 1 month after stopping treatment with isotretinoin, even if you have amenorrhea.

When choosing the method of contraception, individual situations should be considered on a case-by-case basis, involving the patient in the discussion to ensure her commitment and adherence to the methods chosen.

Pregnancy tests

It is recommended to perform pregnancy tests with a sensitivity of at least 25 mIU / mL under medical supervision as follows:

Before starting treatment

A pregnancy test should be performed under medical supervision at least one month after the start of contraception and shortly before (preferably a few days) the first prescription of the drug. The test result should confirm that the patient is not pregnant when initiating treatment with isotretinoin.

Follow-up visits

Follow-up visits should be scheduled at regular intervals, ideally monthly. The need for monthly pregnancy tests under medical supervision should be determined based on local practices and taking into account the woman’s sexual activity, recent menstrual history (abnormal, irregular or amenorrhea) and the contraceptive method used. If indicated, pregnancy tests should be performed as part of the follow-up on the day of the prescribing visit or during the 3 days preceding the visit to the prescriber.

End of treatment

A final pregnancy test should be performed 1 month after the end of treatment.

Prescription and dispensing restrictions

In women of childbearing age, the duration of the prescription of ISOTRETINOINE ACNETRAIT 40 mg, soft capsule should ideally be limited to 30 days in order to facilitate regular monitoring, including the performance of pregnancy tests and monitoring in this regard. Ideally, the pregnancy test, prescription and delivery of ISOTRETINOINE ACNETRAIT 40 mg, soft capsule should take place on the same day. Isotretinoin must be dispensed within a maximum of 7 days following its prescription.

The monthly follow-up will ensure that regular monitoring and pregnancy tests are carried out and that the patient is not pregnant before starting a new course of treatment.

Men

The available data suggest that the level of maternal exposure from the semen of patients treated with ISOTRETINOINE ACNETRAIT 40 mg, soft capsule is not sufficient to be associated with the teratogenic effects of ISOTRETINOINE ACNETRAIT 40 mg, soft capsule. Patients should be reminded that they should not give their medicine to other people, especially women.

Additional Precautions

Patients should never be given this medicine to others and should return any unused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during treatment and for 1 month after stopping treatment with isotretinoin due to the potential risk to the fetuses of pregnant women receiving transfusions.

Information documents

In order to help prescribers, pharmacists and patients avoid fetal exposure to isotretinoin, the Marketing Authorization Holder provides them with information documents aimed at reinforcing the warnings relating to the teratogenicity of isotretinoin, to advise on the establishment of contraception prior to treatment and to provide an explanation of the necessary pregnancy tests.

As part of the Pregnancy Prevention Program, the prescribing physician must inform male and female patients of the expected teratogenic risk and strict pregnancy prevention measures and provide them with an informative brochure.

Psychiatric disorders

Depression, aggravated depression, anxiety, aggressive tendency, mood changes, psychotic symptoms, and very rarely, suicidal ideation, attempted suicide and suicide have been reported in patients treated with isotretinoin (see section Adverse effects ). Special care should be taken in patients with a history of depression and all patients should be monitored for any signs of depression and initiate appropriate therapeutic measures, if necessary. However, stopping treatment with isotretinoin may not be sufficient to alleviate symptoms and further psychiatric or psychological evaluation may be necessary.

Raising awareness among family and friends can be helpful in detecting possible deterioration in mental health.

Skin and subcutaneous tissue disorders

An acute exacerbation of acne is sometimes observed at the start of treatment; it decreases with continued treatment, usually within 7 to 10 days without the need to adjust the doses.

Intense exposure to the sun or UV rays should be avoided. Otherwise, use a sunscreen with a high protection coefficient (SPF greater than or equal to 15).

Aggressive chemical dermabrasions and treatment with dermatological lasers should be avoided during treatment with isotretinoin, as well as during the 5 to 6 months following its discontinuation because of the risk of hypertrophic scars in atypical areas and more rarely of the risk of post-inflammatory hyper- or hypo-pigmentation in the treated areas. Waxing should be avoided during treatment with isotretinoin and at least 6 months after stopping it because of the risk of skin detachment.

The application of local keratolytics or exfoliating antacneics should be avoided during treatment due to an increased risk of local irritation.

It is recommended to regularly apply moisturizers as well as a lip balm from the start of treatment to fight against skin and labial dryness induced by isotretinoin.

Cases of severe skin reactions (such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in patients treated with isotretinoin. As these reactions are difficult to distinguish from other skin reactions that may occur (see section 4.8 ), patients should be warned of the signs and symptoms, and be closely monitored for severe skin reactions. If a severe skin reaction is suspected, treatment with isotretinoin should be discontinued.

Eye disorders

Dry eyes, corneal opacities, decreased night vision and keratitis usually go away after stopping treatment. Dry eyes can be prevented by applying lubricating eye ointment or artificial tears. An intolerance to the wearing of contact lenses may require the use of glasses for the duration of treatment.

Decreased night vision has also been observed, onset in some patients (see section Effects on ability to drive and use machines ). Patients with visual disturbances should be referred to a specialist ophthalmology consultation. Sometimes it is necessary to stop taking isotretinoin.

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia and increased serum creatine phosphokinase (CPK) levels have been observed in patients treated with isotretinoin, especially with intense physical activity (see section 4.8 ).

Skeletal alterations such as premature fusion of the conjugation cartilages, hyperostosis and tendon or ligament calcifications have occurred after administration of very high doses of isotretinoin for several years, in treatment of keratinization disorders. The daily dosages, the durations of treatment and the cumulative doses greatly exceeded in these patients those usually recommended for the treatment of acne.

Benign intracranial hypertension

Benign intracranial hypertension has been observed in patients treated with isotretinoin. Some have occurred with the concomitant use of tetracyclines (see sections 4.3 and Interactions with other medicinal products and other forms of interactions ). Manifestations of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances, and papillary edema. The diagnosis of benign intracranial hypertension requires immediate discontinuation of isotretinoin.

Hepato-biliary disorders

Liver enzymes should be checked before and one month after starting treatment, then every three months, except when special medical circumstances justify more frequent checks. Transient and reversible elevations of hepatic transaminases have been observed. Very often, this increase remains within normal limits and the levels return to their pre-treatment values ​​despite continued treatment. However, in the event of a significant and persistent elevation of transaminases, a reduction in dosage or even discontinuation of isotretinoin should sometimes be considered.

Renal failure

Renal impairment does not influence the pharmacokinetics of isotretinoin. The drug can therefore be prescribed to patients with renal failure. However, it is recommended to start treatment at a low dose and gradually increase to the maximum tolerable dose (see section 4.2 ).

Lipid metabolism disorders

Blood lipids should be checked (on an empty stomach) before and one month after starting treatment, and every three months thereafter, unless closer monitoring is indicated. An increase in blood lipid levels may be observed. It usually resolves after dose reduction or discontinuation of treatment, dietary measures may also be helpful.

Treatment with isotretinoin may cause an increase in serum triglycerides. It should be discontinued when hypertriglyceridemia cannot be controlled to an acceptable level, or if signs of pancreatitis occur (see section 4.8 ). Triglyceride levels above 800 mg / dL (or 9 mmol / L) may be associated with acute pancreatitis, which can sometimes be fatal.

Gastrointestinal disturbances

Treatment with isotretinoin has been associated with flare-ups of inflammatory digestive diseases, including regional ileitis, in patients without a digestive history. Isotretinoin should be discontinued immediately in patients with severe diarrhea (bleeding).

Allergic reactions

Exceptionally, anaphylactic reactions have been reported, sometimes after prior exposure to topical retinoids. Allergic skin reactions are rarely reported. Cases of severe allergic vasculitis, often with purpura (ecchymotic or petechial) of the extremities and systemic manifestations, have been reported. Severe allergic reactions require discontinuation of treatment and close monitoring.

High risk patients

More frequent monitoring of blood lipids and / or blood sugar levels is necessary in certain high-risk patients (diabetes, obesity, alcoholism or lipid metabolism disorders). Elevation of fasting blood sugar has been observed, and new cases of diabetes have developed during treatment with isotretinoin.

Related to excipients

ISOTRETINOINE ACNETRAIT 40 mg, soft capsule contains refined soybean oil, partially hydrogenated soybean oil and hydrogenated soybean oil. If you are allergic to peanuts or soybeans, do not use this medication.

This medicine contains 23.75 mg of sorbitol per soft capsule.

This medicine contains an azo coloring agent (orange yellow S (E110)) and may cause allergic reactions.

This medicine contains less than 1 mmol (23 mg) sodium per soft capsule, that is to say it is essentially “sodium-free”.

Pregnancy and breast feeding

Pregnancy

Pregnancy is an absolute contraindication to treatment with isotretinoin (see section Contraindications “Contraindications”). The occurrence, despite contraceptive measures, of pregnancy during treatment with isotretinoin or in the month following its discontinuation, carries a very high risk of major and serious malformations in the fetus.

The fetal malformations associated with treatment with isotretinoin include anomalies of the central nervous system (hydrocephalus, cerebellar malformations or anomalies, microcephaly), facial dysmorphisms, cleft palates, abnormalities of the outer ear (absence of external ear, auditory canal external small or absent), ocular anomalies (microphthalmos), cardiovascular (conotruncal anomalies such as tetralogy of Fallot, transposition of the great vessels, interventricular communications), anomalies of the thymus and parathyroid glands. There is also an increased risk of spontaneous abortion.

If pregnancy occurs in a woman treated with isotretinoin, treatment should be discontinued and the patient should be referred to a specialist or competent in teratology for evaluation and advice.

Women of childbearing potential / Contraception:

Women of childbearing potential should use at least one effective method of contraception for at least 4 weeks before treatment is started, throughout treatment and up to 4 weeks after treatment with isotretinoin ( see section Warnings and precautions for use ).

Preferably, the patient should use 2 complementary contraceptive methods, including a mechanical method (condoms).

Feeding with milk

Being a highly lipophilic molecule, isotretinoin most likely passes into breast milk. In view of the potential side effects in the mother and the exposed child, isotretinoin is therefore contraindicated during breast-feeding.

Interactions with other drugs and other forms of interactions

Contraindicated associations

+ Vitamin A

Risk of symptoms suggestive of hypervitaminosis A.

+ Other retinoids (acitretin, alitretinoin)

Risk of symptoms suggestive of hypervitaminosis A.

+ Cyclines

Risk of intracranial hypertension.

Other interactions

The concomitant application of local keratolytics or exfoliating antacneics should be avoided during treatment with isotretinoin due to an increased risk of local irritation.

Side effects of Isotretinoin

Summary of the safety profile

The most common side effects seen during treatment with isotretinoin are dryness of the mucous membranes, especially labial (cheilitis), nasal (epistaxis) and eye (conjunctivitis), and dry skin. These and some other side effects are dose dependent. In general, most side effects are reversible after reduction of the dosage or interruption of treatment, some however persist after discontinuation of treatment.

Tabulated list of adverse reactions

Adverse reactions are listed below according to the MedDRA database and by System Organ Class and frequency. Frequencies are defined using the following classification: Very common (≥ 1/10); common (≥ 1/100; <1/10); uncommon (≥ 1 / 1,000; <1/100); rare (≥ 1 / 10,000; <1 / 1,000), very rare (<1 / 10,000), not known (cannot be estimated from the available data).

Infections
Very rareGram-positive bacterial (skin and mucous membrane) infection.
Blood and lymphatic circulation disorders
Very commonAnemia, increased sedimentation rate, thrombocytopenia, thrombocythemia.
FrequentNeutropenia.
Very rareLymphadenopathies.
Immune system disorders
RareAllergic skin reactions, anaphylactic reactions, hypersensitivity.
Metabolism and nutrition disorders
Very rareDiabetes, hyperuricemia.
Psychiatric disorders
RareDepression, aggravated depression, aggressive tendencies, anxiety, mood changes.
Very rarePsychotic disorder, abnormal behavior, suicidal ideation, suicide attempt, suicide.
Nervous system disorders
FrequentHeadache.
Very rareBenign intracranial hypertension, convulsions, drowsiness, dizziness.
Eye disorders
Very commonBlepharitis, conjunctivitis, dry eye, eye irritation.
Very rareBlurred vision, visual disturbances, cataracts, achromatopsia (alteration of color vision), intolerance to the wearing of contact lenses, corneal opacities, decrease in night vision, keratitis, papillary edema (indicating benign intracranial hypertension), photophobia .
Ear and auditory canal disorders
Very rareDecreased hearing.
Vascular disorders
Very rareVasculitis (eg Wegener’s disease, allergic vasculitis).
Respiratory, thoracic and mediastinal disorders
FrequentEpistaxis, nasal dryness, nasopharyngitis.
Very rareBronchospasm (especially in patients with asthma), hoarse voice.
Gastrointestinal disturbances
Very rareColitis, ileitis, dry throat, gastrointestinal bleeding, bloody diarrhea and inflammatory digestive disease, nausea, pancreatitis (see section 4.4 ).
Hepato-biliary disorders
Very commonElevation of transaminases (see section 4.4 ).
Very rareHepatitis.
Skin and subcutaneous tissue disorders
Very commonCheilitis, dermatitis, dry skin, localized desquamation, pruritus, erythematous rash, skin fragility (lesions due to friction).
RareAlopecia.
Very rareAcne fulminans, worsening acne, erythema (facial), exanthema, abnormal hair texture, hirsutism, nail dystrophies, peri-onyxis, photosensitivity reaction, botriomycoma, hyperpigmentation, sweating.
Frequency not knownErythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal and connective tissue effects
Very commonArthralgia, myalgia, back pain (especially in adolescents).
Very rareArthritis, calcifications (ligaments and tendons), premature welding of the epiphyses, exostosis (hyperostosis), reduction in bone density, tendonitis, rhabdomyolysis.
Renal and urinary disorders
Very rareGlomerulonephritis.
Reproductive system and breast disorders Not knownSexual dysfunction including erectile dysfunction and low libido, gynecomastia, vulvovaginal dryness.
General disorders and accidents related to the administration site
Very rareIncreased formation of granulomatous tissue, malaise.
Investigations
Very commonElevation of blood triglycerides, decrease in circulating HDL.
FrequentBlood cholesterol increased, blood sugar increased, hematuria, proteinuria.
Very rareIncreased blood creatine phosphokinase level.

The incidence of adverse events was calculated from pooled clinical study data including 824 patients and from post-marketing data.

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals report any suspected adverse reactions via the national reporting system:

Overdose

Isotretinoin is a derivative of vitamin A. Although its acute toxicity is low, signs of hypervitaminosis A could occur in case of accidental overdose. Symptoms of hypervitaminosis A include severe headache, nausea or vomiting, drowsiness, irritability, and itching. Symptoms of accidental or intentional isotretinoin overdose would probably be comparable, they can be expected to be reversible and self-limiting.

Effect on ability to drive and use machines

Decreased night vision has been observed in some cases during treatment with isotretinoin, in rare cases it persists after discontinuation of treatment. As this side effect can appear suddenly, patients should be informed of this potential risk which requires the utmost caution when driving a vehicle or using machines.

Drowsiness, dizziness and visual disturbances have been very rarely reported. Patients exhibiting these effects should be cautioned not to drive a vehicle, use machinery, or participate in any activity which may put them or others at risk.

Isotretinoin Pharmacological properties

Pharmacotherapeutic group: retinoids in the treatment of acne, ATC code: D10BA01.

Action mechanism

Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of isotretinoin is not yet fully understood, but it has been established that the improvement observed in the clinical picture of severe acne is associated with a suppression of the activity of the sebaceous glands and to a histologically proven decrease in the size of these glands. In addition, isotretinoin has been shown to exert an anti-inflammatory effect in the dermis.

Effects

The formation of comedones and possibly inflammatory acne lesions goes through several stages, including hyperkeratinization of the epithelium of the pilosebaceous follicle followed by obstruction of the pilar infundibulum with retention of keratin and excess sebum. Isotretinoin inhibits the proliferation of sebocytes and seems to promote their de-differentiation into keratinocytes; it therefore reduces the production of sebum, which is the essential substrate for the growth of Propionibacterium acnes, and therefore decreases the colonization of the hair canal by this bacterium.

Absorption

The digestive absorption of isotretinoin is variable, proportional to the dosage for therapeutic doses. Its absolute bioavailability has not been measured because the drug is not available for the intravenous route in humans. However, extrapolation of the results obtained in dogs suggests a variable and rather low systemic bioavailability. When isotretinoin is taken with meals, its bioavailability is twice as high as on an empty stomach.

Distribution

Isotretinoin is strongly bound to plasma proteins, mainly albumin (99.9%). The volume of distribution of isotretinoin in humans has not been determined because isotretinoin is not available intravenously in humans. Little information is available regarding the tissue distribution of isotretinoin in humans. The concentrations of isotretinoin in the epidermis represent only half of the serum concentrations. Plasma concentrations of isotretinoin are approximately 1.7 times those found in blood, due to the poor penetration of isotretinoin into red blood cells.

Metabolism

After oral administration of isotretinoin, three major metabolites have been identified in plasma: 4-oxoisotretinoin, tretinoin (all-trans retinoic acid) and 4-oxotretinoin. These metabolites have shown biological activity in several in vitro tests . A therapeutic trial with the administration of 4-oxoisotretinoin confirmed the important contribution of this molecule to the therapeutic efficacy of isotretinoin (reduction in the rate of sebaceous excretion despite the absence of modification of the blood levels of isotretinoin and tretinoin. ). Other minor metabolites include glycuro-conjugated derivatives. 4-Oxoisotretinoin is the major metabolite. At steady state, the plasma concentration of this metabolite is 2,

Since the conversion of isotretinoin to tretinoin (all-trans retinoic acid) is a reversible reaction (interconversion), the metabolism of tretinoin is therefore linked with that of isotretinoin. It is estimated that 20-30% of the dose of isotretinoin is metabolized by isomerization.

Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans. In vitro metabolism studies have shown that several CYP enzymes are involved in the metabolism of isotretinoin to 4-oxo-isotretinoin and tretinoin. No isomer seems to have a predominant role. Isotretinoin and its metabolites do not have a significant influence on CYP activity.

Elimination

After oral administration of labeled isotretinoin, approximately equivalent amounts are found in urine and faeces. After oral administration of isotretinoin to acne patients, the elimination half-life of the unchanged substance is on average 19 hours. The half-life of 4-oxo-isotretinoin is longer, averaging 29 hours.

Isotretinoin is present in the body in a physiological state and a return to endogenous retinoid concentrations is achieved approximately two weeks after stopping treatment with isotretinoin.

Pharmacokinetics in special clinical situations

As isotretinoin is contraindicated in patients with hepatic impairment, little data is available on the kinetics of the drug in this patient population. Renal impairment does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.

Duration and special precautions for storage

Retention period :

3 years.

Special precautions for storage :

Store at a temperature not exceeding 30 ° C.

Store in the original outer packaging.

At the end of treatment, unused ISOTRETINOINE ACNETRAIT capsules should be returned to the pharmacist.

30 soft capsules in blister packs (PVC / PVDC / Aluminum)

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