Expiration date: 11/2028

Method of administration and dosage

Orally. During meals, 1-2 times a day.

Isotretinoin therapy should be prescribed or supervised by physicians experienced in the use of systemic retinoids for the treatment of severe acne and who have a full understanding of the risks associated with isotretinoin therapy and the monitoring requirements.

Pediatric patients

Isotretinoin should not be used to treat prepubertal acne. Its use is not recommended in children under 12 years of age, as there is no data on its efficacy and safety in this patient group.

Adult patients, adolescents and elderly patients

Isotretinoin treatment should be initiated with a dose of 0.5 mg/kg per day. The therapeutic efficacy of isotretinoin and some of its side effects are dose-dependent and vary among patients. This necessitates individual dose adjustments throughout treatment. For most patients, the dose ranges from 0.5 to 1.0 mg/kg of body weight per day.

The rates of long-term remission and relapse are more closely related to the total course dose than to the duration of therapy or the daily dose. A course dose exceeding 120-150 mg/kg (per treatment course) does not provide significant additional benefit.

The duration of therapy varies depending on the daily dose for individual patients. Complete acne remission is usually achieved within 16-24 weeks of treatment. Most patients experience complete acne resolution after a single course of treatment. If a relapse occurs, a second course of Verocutan is recommended at the same daily and course dose as the first. Since improvement can last up to 8 weeks after discontinuing the drug, a second course should not be prescribed before this period has elapsed.

Special patient groups

Patients with impaired renal function

In patients with severe renal impairment, isotretinoin treatment should be initiated at a lower dose (e.g., 10 mg/day) and then increased to 1 mg/kg/day or the maximum tolerated dose (see section 4.4).

Patients with intolerance

In patients with severe intolerance to the recommended dose, treatment may be continued at a lower dose, taking into account the consequences of longer therapy and the higher risk of relapse. To achieve maximum efficacy in these patients, treatment should generally be continued at the maximum tolerated dose.

Indications

• Severe forms of acne (nodulocystic acne, conglobate acne, or acne with a risk of scarring)
• Acne that does not respond to other treatments

Compound

Composition per capsule:

Active ingredient

Isotretinoin 20 mg

Excipients

sufficient to obtain the contents of a capsule weighing 328 mg

[Soybean oil, purified 266.88 mg

Beeswax 1.64 mg

Hydrogenated soybean oil 39.36 mg

Butylated hydroxyanisole 0.08 mg

Disodium edetate (Trilon B) 0.04 mg

Excipients

sufficient to obtain the contents of a capsule weighing 192 mg

[Medical gelatin 139.748 mg

Glycerol (glycerin) 50.45 mg

Methyl parahydroxybenzoate (Methylparaben) 0.98 mg

Propyl parahydroxybenzoate (propylparaben) 0.14 mg

Titanium dioxide 0.634 mg

Iron oxide red dye 0.048 mg

Contraindications

History of hypersensitivity to isotretinoin or any of the excipients in the drug, including soy and peanuts.

Liver failure

Hypervitaminosis A

Concomitant therapy with tetracyclines

Children under 12 years of age

Severe hyperlipidemia

Pregnancy

Breastfeeding period

Women of childbearing potential, unless the woman's condition meets all the criteria of the Pregnancy Prevention Program

With caution

History of depression

Diabetes mellitus

Obesity

Lipid metabolism disorder

Alcoholism

Special instructions

Teratogenic effects

Isotretinoin is a potent teratogen that frequently causes severe and life-threatening birth defects in humans.

Isotretinoin is strictly contraindicated:

• pregnant women;
• women of childbearing potential, unless the woman's condition meets all the criteria of the Pregnancy Prevention Program.
• Pregnancy Prevention Program
• Isotretinoin is a drug with a TERATOGENIC effect.

Isotretinoin is contraindicated in women of childbearing potential unless the woman's condition meets all of the following criteria of the Pregnancy Prevention Program:

• severe forms of acne (nodulocystic, conglobate acne or acne with the risk of scarring), acne that does not respond to other types of therapy (see section “Indications for use”);
• the possibility of pregnancy should be assessed for all patients;
• the patient must understand the teratogenic risk;
• the patient must understand the need for a mandatory visit to the doctor every month;
• The patient must understand and continuously use effective contraceptive methods for one month before, during, and one month after treatment with isotretinoin. At least one highly effective contraceptive method (i.e., a contraceptive method that is not user-dependent) or two different contraceptive methods simultaneously (which are user-dependent) must be used.

When choosing a method of contraception in each individual case, individual circumstances should be assessed, with the patient involved in the discussion in order to ensure her commitment and use of the chosen method of contraception;

Even in case of amenorrhea, it is necessary to follow all recommendations for effective contraception;

the patient must be informed and understand the potential consequences of pregnancy and the need for urgent consultation in cases where there is a risk of pregnancy or she may be pregnant;

the patient understands the need for and consents to undergo regular pregnancy tests before the start of therapy, preferably monthly during therapy and 1 month after completion of therapy;

The patient confirms understanding of 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 doctor considers that there are compelling reasons indicating that there is no risk of pregnancy.

The physician must be sure that:

the patient meets all of the above conditions for contraception, including confirmation that she has an adequate level of understanding;

the patient is familiar with the above conditions;

the patient understands the need for consistent and correct use of one highly effective method of contraception (i.e. a contraceptive method that is not user-dependent) or 2 different methods of contraception simultaneously (that are user-dependent) for at least one month before starting treatment with isotretinoin, during treatment, and for at least one month after its completion;

a negative pregnancy test result was obtained before starting treatment, during therapy, and one month after the end of therapy; the dates and results of the pregnancy test should be documented.

If pregnancy occurs in a patient receiving isotretinoin, treatment should be discontinued and the patient should be referred to a physician specializing in or experienced in teratology for evaluation and advice. If pregnancy occurs after treatment has been discontinued, the risk of severe and major fetal malformations remains until the drug is completely eliminated from the body, which typically occurs one month after the end of therapy.

Contraception

Patients should be provided with comprehensive information on contraception and recommendations for those not using effective contraception. If the treating physician cannot provide such information, the patient should be referred to another physician with appropriate specialization and qualifications.

The minimum requirement is the use of one highly effective contraceptive method (i.e., a contraceptive method that is not user-dependent) or two different contraceptive methods simultaneously (user-dependent) for at least one month before starting isotretinoin treatment, during treatment, and for at least one month after its completion, even in patients with amenorrhea. When choosing a contraceptive method in each individual case, individual circumstances should be assessed, with the patient involved in the discussion to ensure her commitment and use of the chosen contraceptive method.

Pregnancy test

In accordance with local practice, a pregnancy test with a minimum sensitivity of 25 mIU/mL should be performed under the guidance of a healthcare professional according to the following recommendations.

Before starting therapy

A pregnancy test should be performed at least one month after initiating contraception and as soon as possible (preferably a few days) before the initial prescription. This pregnancy test should be performed under the supervision of a healthcare professional. This test ensures that the patient is not pregnant before starting isotretinoin.

During therapy

The patient should see a doctor regularly, preferably monthly. The need for monthly pregnancy testing is determined by local practice and takes into account sexual activity, previous menstrual irregularities (abnormal menstruation, missed menstruation, amenorrhea), and contraception. If indicated, a pregnancy test is performed on the day of the visit or three days prior.

End of therapy

One month after the end of therapy, a final test is performed to exclude pregnancy.

Prescription and dispensing of the drug

A prescription for Verocutan for a woman of childbearing potential should be written, preferably for 30 days of treatment, to ensure regular monitoring, including pregnancy tests and monitoring. It is recommended that the pregnancy test, prescription, and medication dispensing be completed on the same day.

Verocutan should be dispensed from the pharmacy on the same day and within no more than 7 days from the date of prescription.

Monthly visits will allow for regular pregnancy testing and monitoring to ensure the patient is not pregnant before starting the next cycle of treatment.

For male patients

Available data indicate that drug exposure from semen and seminal fluid of men taking Verocutan is not sufficient to produce teratogenic effects in women.

The drug must not be passed on to other persons, especially women.

Additional precautions

Patients should be instructed not to share Verocutan with others and to dispose of unused capsules in accordance with local guidelines.

To avoid accidental exposure of the fetus to the drug (in case of pregnancy of the recipient during transfusion), donor blood should not be taken from patients who are receiving or have received isotretinoin within a month before.

The physician must provide full information about the teratogenic risk and strict adherence to contraceptive measures according to the Pregnancy Prevention Program to both men and women.

Mental disorders

Patients receiving isotretinoin have reported depression, worsening depression, anxiety, aggressive tendencies, mood swings, psychotic symptoms, and very rare cases of suicidal behavior, suicide attempts, and suicide (see "Side Effects"). Particular caution should be exercised in patients with a history of depression, and all patients should be monitored for signs of depression during treatment, with referral to an appropriate specialist if necessary. However, discontinuing isotretinoin may not resolve symptoms, and further monitoring and treatment by an appropriate specialist may be necessary. Notifying family or friends may be helpful in detecting any deterioration in mental health.

Skin and subcutaneous tissue disorders

In rare cases, acne flare-ups may occur at the beginning of therapy, but these usually resolve within 7-10 days without dose adjustment.

Limit exposure to sunlight and ultraviolet rays. If necessary, use sunscreen with a high sun protection factor (SPF) of at least 15.

Deep chemical dermabrasion and laser treatments should be avoided in patients receiving isotretinoin, as well as for 5-6 months after completion of treatment, due to the potential for increased scarring in atypical areas and (less commonly) the development of post-inflammatory hyper- and hypopigmentation. Waxing should be avoided during isotretinoin treatment and for at least 6 months afterward due to the risk of epidermal detachment.

Concomitant use of isotretinoin with topical keratolytic or exfoliative acne medications should be avoided due to the potential for increased local irritation (see section "Interaction with other medicinal products").

Patients receiving isotretinoin are advised to use a moisturizing body ointment or cream, lip balm to reduce dryness of the skin and mucous membranes from the beginning of therapy, since dry skin and lips are likely to occur when using isotretinoin.

During postmarketing surveillance, cases of severe skin reactions, such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with isotretinoin use. These events may be difficult to distinguish from other skin reactions that occur with isotretinoin (see "Side Effects"). Patients should be informed of the signs and symptoms and closely monitored for severe skin reactions. If a severe skin reaction is suspected, isotretinoin should be discontinued.

Allergic reactions

Anaphylactic reactions were rare, and in some cases, they occurred only after previous topical use of retinoids. Allergic skin reactions were reported in rare cases. Severe cases of allergic vasculitis have been observed, often accompanied by purpura (bruises and red spots) on the extremities and outside the skin. Severe allergic reactions require discontinuation of the drug and close patient monitoring.

Visual disturbances

Conjunctival dryness, corneal opacities, impaired twilight vision, and keratitis usually resolve after discontinuing the medication. For dry mucous membranes, moisturizing eye ointment or artificial tears can be applied. If contact lens wear is intolerant, glasses should be worn during treatment.

Impaired twilight vision has been observed with the drug; this phenomenon occurred suddenly in some patients (see the section "Effects on the ability to drive and use machines"). Patients complaining of vision problems should be referred to an ophthalmologist, and consideration should be given to discontinuing isotretinoin.

Musculoskeletal and connective tissue disorders

Arthralgia and myalgia, as well as increased serum CPK activity, have been reported with isotretinoin use, especially in patients undergoing intense physical activity (see "Side Effects"). In some cases, these events may progress to potentially life-threatening rhabdomyolysis.

Several years after using very high doses of isotretinoin for the treatment of dyskeratosis, bone changes developed, including premature closure of epiphyseal growth plates, hyperostosis, and calcification of ligaments and tendons. The dose, duration of therapy, and total course dose in these patients typically significantly exceeded those recommended for acne treatment.

Benign intracranial hypertension

Cases of benign intracranial hypertension have been reported, in some cases with concomitant use with tetracyclines (see sections "Contraindications" and "Drug Interactions"). Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances, and papilledema. In such patients, isotretinoin should be discontinued immediately.

Liver and biliary tract disorders

Monitoring liver enzymes is recommended before treatment, 1 month after initiation, and then every 3 months or as needed. Transient and reversible increases in liver transaminases have been observed. In most cases, these increases were within normal limits and returned to baseline during therapy. However, if persistent, clinically significant increases in liver transaminases occur, the dose should be reduced or the drug discontinued.

Renal failure

Renal insufficiency and renal impairment do not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be used in patients with renal insufficiency. However, in these patients, isotretinoin treatment is recommended to begin with a lower dose and then titrate to the maximum tolerated dose (see "Dosage and Administration").

Lipid metabolism

Fasting serum lipid levels should be measured before treatment, 1 month after initiation, and then every 3 months or as indicated. Lipid levels typically return to normal after dose reduction or discontinuation of the drug, as well as with dietary intervention.

Isotretinoin use has been associated with increased plasma triglyceride levels. If hypertriglyceridemia cannot be controlled to an acceptable level or if symptoms of pancreatitis occur, isotretinoin should be discontinued (see "Side Effects"). Triglyceride levels exceeding 800 mg/dL or 9 mmol/L may lead to acute pancreatitis, which can be fatal.

Gastrointestinal disorders

Inflammatory bowel disease (including regional ileitis) has been reported with isotretinoin therapy in patients without a history of bowel disorders. Isotretinoin should be discontinued immediately in patients with severe (hemorrhagic) diarrhea.

High-risk patients

High-risk patients (those with diabetes, obesity, alcoholism, or lipid metabolism disorders) may require more frequent laboratory monitoring of serum glucose and/or lipid levels during isotretinoin treatment. Increased fasting blood sugar levels and new-onset diabetes have been reported with isotretinoin use.

Disposal of unused/expired medication

The release of medicinal products into the environment should be minimized. Verocutan should not be disposed of via wastewater or household waste. Whenever possible, use dedicated medicinal product disposal systems.

Excipients: This medication contains the following excipients: methyl parahydroxybenzoate (methylparaben) and propyl parahydroxybenzoate (propylparaben). These substances may cause allergic reactions (including delayed reactions) when taken orally.

Packaging and release form

Capsules 20 mg - 30 pcs per pack, together with instructions for use in a cardboard box.

Side effects

Safety Profile Summary

Some side effects associated with isotretinoin are dose-dependent. These side effects are generally reversible with dose adjustments or discontinuation of the drug, but some may persist after treatment is stopped. The most common symptoms reported as side effects with isotretinoin include dry skin, mucous membranes such as the lips (cheilitis), nosebleeds, and eyes (conjunctivitis).

Adverse reactions observed during clinical trials (824 patients) and post-marketing use are presented below according to MedDRA system organ classes.

The frequency of adverse reactions is classified as follows: 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), and not known (cannot be estimated from the available data). Within each frequency category and system organ class, adverse reactions are presented in order of decreasing seriousness.

Infectious and parasitic diseases: very rare - bacterial infections (skin and mucous membranes) caused by gram-positive pathogens.

Blood and lymphatic system disorders: very common thrombocytopenia, anemia, thrombocytosis, increased erythrocyte sedimentation rate; common - neutropenia; very rare - lymphadenopathy.

Immune system disorders: rare - anaphylactic reactions, hypersensitivity, skin allergic reactions.

Metabolism and nutrition disorders: very rare - diabetes mellitus, hyperuricemia.

Psychiatric disorders: rare - depression, increased depression, tendency to aggression, anxiety, mood swings; very rare - suicide, suicide attempts, suicidal behavior, psychotic disorder, abnormal behavior.

Nervous system disorders: common - headache; very rare - benign intracranial hypertension, seizures, drowsiness, dizziness.

Visual disturbances: very common - blepharitis, conjunctivitis, dry eyes, eye irritation; very rare - papilledema (as a sign of benign intracranial hypertension), cataract, color anomaly (impaired color perception), contact lens intolerance, corneal opacity, impaired twilight vision, keratitis, photophobia, visual impairment, blurred vision.

Ear and labyrinthine disorders: very rare - hearing impairment.

Vascular disorders: very rare - vasculitis (eg, Wegener's granulomatosis, allergic vasculitis).

Respiratory system, chest and mediastinal disorders: common - nasopharyngitis, nosebleed, dry nasal mucosa; very rare - bronchospasm (especially in patients with asthma), dysphonia.

Gastrointestinal disorders: very rare - inflammatory bowel disease, colitis, ileitis, pancreatitis, gastrointestinal bleeding, hemorrhagic diarrhea, nausea, dry throat.

Liver and biliary tract disorders: very common - increased activity of liver transaminases; very rare - hepatitis.

Skin and subcutaneous tissue disorders: very common - pruritus, erythematous rash, dermatitis, cheilitis, dry skin, localized exfoliation, skin fragility (risk of damage from friction); rare - alopecia; very rare - acne fulminant, acne exacerbation, erythema (on the face), exanthema, hair disorder, hirsutism, nail dystrophy, paronychia, photosensitivity reactions, pyogenic granuloma, skin hyperpigmentation, increased sweating; unknown - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: very common - arthralgia, myalgia, back pain (especially in children and adolescents); very rare - arthritis, calcification (calcification of tendons and ligaments), premature closure of epiphyseal growth plates, exostosis (hyperostosis), decreased bone density, tendonitis; unknown - rhabdomyolysis.

Renal and urinary tract disorders: very rare - glomerulonephritis.

Disorders of the genitourinary system and mammary gland: unknown - sexual dysfunction (including erectile dysfunction and decreased libido), gynecomastia.

General disorders and administration site conditions: very rare - proliferation of granulation tissue, malaise.

Laboratory and instrumental data: very often - increased blood triglycerides, decreased high-density lipoproteins; often - increased blood cholesterol, increased blood glucose, hematuria, proteinuria; very rarely - increased creatine phosphokinase activity in the blood

Pharmacotherapeutic group

acne medications; systemic acne medications; acne retinoids

Interaction with other drugs

Vitamin A and isotretinoin should not be used simultaneously due to the risk of developing hypervitaminosis A.

Cases of benign intracranial hypertension ("pseudotumor cerebri") have been observed with the concomitant use of tetracyclines and isotretinoin.

Therefore, the use of tetracyclines concomitantly with isotretinoin should be avoided (see sections “Contraindications” and “Special instructions”).

Concomitant use with topical keratolytic or exfoliative acne treatments should be avoided due to possible increased local irritation (see section "Special instructions").

Impact on the ability to drive a car and operate other machinery

Verocutan may affect the ability to drive and operate machinery. Impaired twilight vision has been observed during isotretinoin therapy, and in rare cases, this may persist after discontinuation of therapy (see "Side Effects" and "Special Instructions"). Since this phenomenon has occurred suddenly in some patients, patients should be informed of the possibility of this condition and advised to exercise caution when driving and operating machinery.

Although drowsiness, dizziness and visual disturbances have been observed very rarely, patients should be warned that if these events occur they should not drive vehicles, operate machinery or perform activities that pose a risk to the patient or others.

Use during pregnancy and breastfeeding

Use during pregnancy and breastfeeding

WARNING! MAY CAUSE SERIOUS HARM TO AN UNBORN BABY.

Do not use if you are pregnant or think you may be pregnant. Pregnancy is an absolute contraindication for isotretinoin therapy (see Contraindications). Women of childbearing potential must use effective contraception during treatment and for one month after completion of therapy.

If pregnancy occurs despite warnings during treatment with Verocutan or within one month after stopping therapy, there is a very high risk of the baby being born with very severe and serious birth defects.

Congenital malformations associated with isotretinoin use include central nervous system malformations (hydrocephalus, microcephaly, cerebellar malformations/anomalies), facial dysmorphism, cleft palate, external ear anomalies (absence of the outer ear, narrowing or absence of the external auditory canal), eye anomalies (microphthalmia), cardiovascular anomalies (conotruncal malformations such as tetralogy of Fallot, transposition of the great vessels, septal defects), and thymus and parathyroid gland anomalies. An increased incidence of spontaneous abortions has also been reported.

If pregnancy occurs in a patient receiving isotretinoin, therapy should be discontinued. The situation should be discussed with a physician specializing in or experienced in teratology for evaluation and advice.

Breast-feeding

Because isotretinoin is highly lipophilic, it is highly likely to be excreted into breast milk. Due to potential side effects, Verocutan is contraindicated during breastfeeding (see "Contraindications").

Fertility

Isotretinoin in therapeutic doses does not affect the number, motility and morphology of sperm, and does not disrupt the formation and development of the embryo when a man uses isotretinoin.

Pharmacodynamics

Mechanism of action

Isotretinoin is a stereoisomer of all-trans-retinoic acid (tretinoin). The exact mechanism of action of isotretinoin has not yet been elucidated, but it has been established that improvement in the clinical picture of severe acne is associated with the suppression of sebaceous gland activity and a histologically confirmed reduction in their size. Furthermore, isotretinoin has been proven to have an anti-inflammatory effect on the skin.

Clinical efficacy and safety

Hyperkeratosis of the hair follicle and sebaceous gland epithelial cells leads to the shedding of corneocytes into the gland duct, leading to its blockage with keratin and excess sebum. This leads to comedone formation and, in some cases, inflammation. Isotretinoin inhibits sebocyte proliferation and acts on acne by restoring normal cell differentiation. Sebum is the primary growth substrate for Propionibacterium acnes, so reducing sebum production inhibits bacterial colonization of the duct.

Preclinical safety data

Acute toxicity

The acute toxicity of isotretinoin following oral administration has been determined in various animal species. The lethal dose (LD50) is approximately 2000 mg/kg in rabbits, approximately 3000 mg/kg in mice, and greater than 4000 mg/kg in rats.

Chronic toxicity

A long-term 2-year study in rats (isotretinoin doses of 2, 8, and 32 mg/kg/day) revealed partial hair loss and increased plasma triglyceride levels in the higher-dose groups. Thus, the spectrum of adverse effects of isotretinoin in rodents is very similar to that of vitamin A, with the exception of massive tissue and organ calcification observed with vitamin A in rats. No cellular changes were observed with isotretinoin compared to vitamin A.

All observed adverse events of hypervitaminosis A syndrome were spontaneously reversible after discontinuation of isotretinoin. Even in the poor general condition of the study animals, most recovered within 1-2 weeks.

Teratogenicity

Animal studies have shown that isotretinoin, like other vitamin A derivatives, is teratogenic and embryotoxic.

Due to the teratogenic potential of isotretinoin, its use in women of childbearing potential may have therapeutic consequences (see sections

"Contraindications", "Special instructions", "Use during pregnancy and breastfeeding").

Mutagenicity

Isotretinoin has not been shown to be mutagenic in animal studies in vitro or in vivo.

Storage temperature

from 2℃ to 25℃

Dosage form

Soft gelatin capsules, two-color: one half is brown-red, the other half is white with a yellowish tint, oblong in shape with a longitudinal seam

The contents of the capsules are a homogeneous oily suspension from yellow to dark yellow in color.

Pharmacokinetics

Suction

Isotretinoin absorption from the gastrointestinal tract varies and is linearly dependent on the administered dose within the therapeutic range. The absolute bioavailability of isotretinoin has not been determined, as the drug is not available in a human intravenous formulation. However, extrapolation of data obtained in a dog experiment suggests a relatively low and variable systemic bioavailability. Administration of isotretinoin with food increases bioavailability by 2-fold compared to administration on an empty stomach.

Distribution

Isotretinoin is highly bound to plasma proteins, primarily albumin (99.9%). The volume of distribution of isotretinoin in humans has not been determined, as no intravenous dosage form exists. Data on tissue distribution of isotretinoin in humans are insufficient. Isotretinoin concentrations in the epidermis are half those in serum. Plasma isotretinoin concentrations are approximately 1.7 times higher than blood concentrations due to poor penetration of isotretinoin into red blood cells.

Metabolism

Following oral administration of the 4-oxo metabolite, three major metabolites are found in plasma: isotretinoin, tretinoin (all-trans retinoic acid), and 4-oxo-tretinoin. These metabolites possess biological activity, confirmed in several in vitro tests. In a clinical study, 4-oxo-isotretinoin was shown to significantly contribute to the activity of isotretinoin (reduced sebum formation, despite having no effect on plasma concentrations of isotretinoin and tretinoin). Less significant metabolites, including glucuronide conjugates, were also detected. The major metabolite is 4-oxo-isotretinoin, with steady-state plasma concentrations 2.5 times higher than those of the parent compound.

Because isotretinoin and tretinoin (all-trans retinoic acid) are reversibly converted to each other, tretinoin metabolism is linked to that of isotretinoin. It has been estimated that 20-30% of the isotretinoin dose 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 cytochrome P450 (CYP) enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. No single isoform appears to play a dominant role. Isotretinoin and its metabolites do not significantly affect the activity of CYP enzymes.

Withdrawal

Following oral administration of radiolabeled isotretinoin, approximately equal amounts are recovered in urine and feces. The terminal half-life of unchanged drug in acne patients averages 19 hours after oral administration of isotretinoin. The terminal half-life of 4-oxo-isotretinoin is longer, averaging 29 hours.

Isotretinoin is a natural (physiological) retinoid. Endogenous retinoid concentrations are restored approximately 2 weeks after discontinuing isotretinoin treatment.

Special patient groups

Liver failure

Because isotretinoin is contraindicated in patients with impaired liver function, data on the pharmacokinetics of the drug in this patient group are limited.

Renal failure

In patients with renal impairment, plasma clearance of isotretinoin or 4-oxo-isotretinoin is not significantly reduced.

Overdose

Isotretinoin is a vitamin A derivative. Despite its low acute toxicity, signs of hypervitaminosis A may occur with accidental overdose. Symptoms of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and itching.

The signs and symptoms of accidental or intentional isotretinoin overdose are likely to be similar. These symptoms are expected to be reversible and resolve without the need for treatment.