Instructions for Roaccutane capsules 20 mg blister No. 30
Composition
active ingredient: isotretinoin;
1 capsule contains 10 mg or 20 mg of isotretinoin;
excipients: yellow beeswax, hydrogenated soybean oil, partially hydrogenated soybean oil, refined soybean oil;
capsule shell: gelatin, glycerol (85%), dry substance Karion 83 (sorbitol (E 420), mannitol (E 421), hydrolyzed hydrogenated starch), titanium dioxide (E 171), red iron oxide (E 172), printing ink.
Dosage form
Capsules.
Main physicochemical properties: 10 mg capsules: oval opaque capsules of brown-red color, clear imprint of “ROA 10” on the surface of the capsule, capsule length 8.3 – 10.7 mm, capsule diameter 5.3 – 7.7 mm; capsule contents - homogeneous suspension of dark yellow color;
20 mg capsules: oval opaque capsules, one half is brownish-red, the other half is white, the surface of the capsule has a clear imprint of “ROA 20”, the length of the capsules is 12.4 – 14.2 mm, the diameter of the capsules is 7.3 – 9.1 mm; the contents of the capsule are a homogeneous suspension of dark yellow color.
Pharmacotherapeutic group
Means for systemic treatment of acne.
ATX code D10B A01.
Pharmacological properties
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 fully elucidated, but it has been shown that improvement in severe acne is associated with decreased sebaceous gland activity and histologically confirmed reduction in sebaceous gland size. In addition, isotretinoin has been shown to have anti-inflammatory effects on the skin.
Efficiency
Hyperkeratosis of the epithelial cells of the hair follicle and sebaceous gland leads to the exfoliation of corneocytes into the duct of the gland and to the blockage of the latter with keratin and excess sebum. After which a comedone is formed and in some cases an inflammatory process joins. Roaccutane® inhibits the proliferation of sebocytes and acts on acne, restoring the normal process of cell differentiation. Sebum is the main substrate for the growth of Propinibacterium acnes, a decrease in sebum production inhibits bacterial colonization of the duct.
Pharmacokinetics
Absorption
The absorption of isotretinoin from the gastrointestinal tract is variable and linearly dependent on the dose of the drug in the therapeutic dosage range. The absolute bioavailability of isotretinoin has not been determined, since there is no dosage form for intravenous administration, but extrapolation of the results of a study in dogs suggests a very low and variable systemic bioavailability. Taking isotretinoin with food increases its bioavailability by twofold compared with taking it on an empty stomach.
Distribution
Isotretinoin is almost completely bound to plasma proteins (99.9%), mainly albumin. The volume of distribution of isotretinoin in humans is unknown, as there is no intravenous formulation. Epidermal concentrations of isotretinoin are only half those in serum. Plasma concentrations of isotretinoin are approximately 1.7 times higher than whole blood concentrations due to poor penetration of isotretinoin into erythrocytes.
Metabolism
After oral administration, three major metabolites are observed in plasma: 4-oxo-isotretinoin, tretinoin (all-trans-retinoic acid), and 4-oxo-retinoin. These metabolites have demonstrated biological activity in several in vitro tests. 4-oxo-isotretinoin has been shown in several clinical studies to contribute significantly to the therapeutic activity of isotretinoin (sebum suppression, independent of plasma levels of isotretinoin and tretinoin). The major metabolite is 4-oxo-isotretinoin, with steady-state plasma concentrations 2.5-fold higher than those of the parent drug. Other metabolites, including glucuronide conjugates, are minor.
Since isotretinoin and tretinoin (all-trans-retinoic acid) are interconvertible, the metabolism of tretinoin is linked to that of isotretinoin. It has been estimated that 20-30% of an 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 CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. No one isoform appears to play a dominant role. Roaccutane® and its metabolites have no significant effect on the activity of CYP enzymes.
Breeding
After oral administration of radiolabeled isotretinoin, approximately equal amounts of isotretinoin are recovered in urine and feces. The terminal elimination half-life of the unchanged drug after oral administration to acne patients averages 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer, averaging 29 hours.
Isotretinoin belongs to the natural (physiological) retinoids. Endogenous retinoid concentrations are restored approximately 2 weeks after stopping Roaccutane®.
Pharmacokinetics in special clinical cases
Renal insufficiency does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.
Indication
Severe forms of acne (including nodular and conglobatic acne, acne with a tendency to permanent scarring) that are not amenable to standard treatment methods (systemic antibacterial therapy, topical treatment).
Contraindication
Pregnancy and breastfeeding; in women of reproductive age if all conditions of the "Pregnancy Prevention Program" are not met; hypersensitivity to isotretinoin or to any of the components of the drug; hepatic insufficiency; severe hyperlipidemia; hypervitaminosis A; concomitant therapy with tetracyclines. Due to the fact that Roaccutane® contains soybean oil, partially hydrogenated soybean oil and hydrogenated soybean oil, the drug is contraindicated for use in patients with soy allergy.
Interaction with other medicinal products and other types of interactions
Due to possible exacerbation of symptoms of hypervitaminosis A, the simultaneous administration of Roaccutane® and vitamin A should be avoided.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of isotretinoin with tetracyclines. Therefore, concomitant use with tetracyclines should be avoided (see sections 4.3 and 4.4).
Combined use with topical keratolytic or exfoliative drugs for the treatment of acne is contraindicated due to possible increased local irritation (see section "Special instructions").
Application features
"Pregnancy Prevention Program"
This drug is TERATOGENIC.
Roaccutane® is contraindicated in women of reproductive age unless all of the following conditions are met:
– a woman has been diagnosed with a severe form of acne (nodular and conglobatic acne, acne with a tendency to permanent scarring), which is not amenable to standard treatment methods (systemic antibacterial therapy, topical treatment);
– the woman understands the teratogenic risk of the drug;
– the woman understands the need for a mandatory visit to the doctor every month;
– a woman is able to prevent pregnancy by continuously using reliable contraception for 1 month before starting treatment with Roaccutane®, during treatment and for a month after the end of treatment; it is advisable to use 2 different methods of contraception simultaneously, including a barrier method;
– even with amenorrhea, a woman should use reliable contraception;
– the woman must confirm that she understands the essence of the precautions;
– the woman is informed about the risk of pregnancy during treatment with Roaccutane® and understands the need to seek immediate advice if pregnancy is suspected;
– the woman understands the need and agrees to a pregnancy test before, during and 5 weeks after treatment;
– the woman confirms that she is aware of the dangers of using isotretinoin and the need for precautions;
– a woman should start treatment with Roaccutane® only on the 2nd or 3rd day of the next normal menstrual cycle.
The use of contraceptives according to the above recommendations during treatment with isotretinoin is necessary even for sexually inactive women, except in cases where the doctor is sure that there is no risk of pregnancy.
The doctor must be sure that:
– the patient is able to understand and comply with all of the above conditions for preventing pregnancy, and that the patient has an appropriate level of understanding;
– the patient uses at least one, and preferably two, effective methods of contraception, including a barrier method, for 1 month before starting treatment with Roaccutane®, during treatment and for a month after the end of treatment;
– a negative result of a reliable pregnancy test was obtained before starting the drug, during treatment and 5 weeks after the end of therapy. The dates and results of the pregnancy test must be documented.
Pregnancy prevention.
Patients should be informed about contraceptive methods. If they are not using effective contraception, the physician should provide appropriate advice.
Women at risk of pregnancy should use at least one effective method of contraception. It is preferable to use two complementary methods of contraception, including a barrier method. Contraceptive methods should be continued for at least 1 month after stopping treatment with Roaccutane®, even in patients with amenorrhea.
Pregnancy test.
According to current practice, a pregnancy test with a minimum sensitivity of 25 mIU/ml should be performed in the first 3 days of the menstrual cycle.
Before starting treatment
A pregnancy test is performed on the day of Roaccutane® administration or 3 days before the patient's visit to the doctor. The specialist should record the test results. The drug can only be prescribed to patients who have been receiving effective contraception for at least 1 month before starting treatment with Roaccutane®. The test should ensure that the patient is not pregnant at the time of starting treatment with isotretinoin.
During treatment
The patient should visit the doctor every 28 days. The need for monthly pregnancy testing is determined according to local practice and taking into account sexual activity and recent menstrual history (abnormal menstruation, amenorrhea or amenorrhea). If indicated, a pregnancy test is performed on the day of the visit or 3 days before the visit.
Completion of treatment
5 weeks after the end of treatment, a final test is performed to rule out pregnancy.
The pharmacist must ensure that a prescription for Roaccutane® to a woman of reproductive age is only for 30 days of treatment; continued treatment requires a new prescription from a doctor.
It is recommended that pregnancy testing, prescription writing and collection of the medication be completed within the same day. Roaccutane® should only be dispensed by the pharmacy within 7 days of the prescription being issued.
Male patients.
Available data suggest that in women, exposure to the drug from the semen and seminal fluid of men taking Roaccutane® is insufficient to produce teratogenic effects of Roaccutane®.
Men should exclude the possibility of the drug being used by other people, especially women.
Additional warnings
Microdose progesterone preparations may be an inadequate method of contraception during treatment with Roaccutane®.
Patients should never give this medicine to other people and should return any unused capsules to their doctor after treatment is finished.
Patients should not donate blood during treatment and for 1 month after its discontinuation, as there is a risk of transfusion transmission to the fetus of a pregnant woman.
Educational materials
To help doctors, pharmacists and patients avoid the risk of Roaccutane® exposure to the fetus, the manufacturing company provides educational materials aimed at preventing the teratogenic effects of the drug, recommendations on the use of contraception before starting therapy and on the need for pregnancy testing.
Complete information about teratogenic risk and pregnancy prevention measures is contained in the "Pregnancy Prevention Program", which must be provided to all patients - both men and women.
Mental disorders
Depression, aggravated depression, anxiety, aggressive tendencies, mood swings, psychotic symptoms and very rarely suicidal thoughts, suicide attempts and suicide have been reported in patients treated with Roaccutane® (see section 4.8). Caution should be exercised in patients with a history of depression and patients should be monitored for signs of depression during treatment and referred to appropriate specialists if necessary. However, discontinuation of Roaccutane
® may not eliminate the symptoms of psychiatric disorders, in which case the patient needs further supervision by specialists.
Skin and subcutaneous tissue disorders
In rare cases, at the beginning of therapy, an exacerbation of acne is observed, which usually resolves after 7-10 days without adjusting the dose of the drug.
Excessive exposure to sunlight or UV rays should be avoided. If sun protection is necessary, use sunscreen with an SPF of at least 15.
Deep chemical dermabrasion and laser treatment should not be performed during treatment with Roaccutane® and for 5-6 months after treatment, as there is a high risk of hypertrophic scars in atypical areas and, less commonly, hyper- and hypopigmentation in the treatment areas. Waxing should not be performed during treatment with Roaccutane® and for 6 months after treatment due to the risk of epidermal detachment.
The concomitant use of Roaccutane® with topical keratolytic or exfoliative agents for the treatment of acne should be avoided due to the possibility of increased local irritation (see section “Interaction with other medicinal products and other types of interactions”).
Patients receiving Roaccutane® are advised to use moisturizing ointments or body creams, lip balm to reduce dryness of the skin and lips at the beginning of treatment.
In the post-marketing period, cases of severe skin reactions (erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Since these cases can be difficult to distinguish from other skin reactions that may occur (see section "Adverse reactions"), patients should be warned about the symptoms of these diseases and carefully monitored for severe skin reactions. If severe skin reactions are suspected, isotretinoin treatment should be discontinued.
Anaphylactic reactions have been reported rarely, in some cases following topical retinoids. Allergic skin reactions have been reported uncommonly. Serious cases of allergic vasculitis of the extremities, often with purpura (bruising and red spots), and non-cutaneous manifestations, have been reported. Serious allergic reactions require discontinuation of therapy and careful monitoring of the patient.
Vision disorders
Dry eyes, corneal clouding, impaired night vision and keratitis usually resolve after discontinuation of the drug. In case of dryness of the mucous membrane of the eye, moisturizing eye ointment or artificial tears can be used. In case of intolerance to contact lenses, glasses should be used during treatment.
Some patients may experience a decrease in night vision, sometimes occurring suddenly (see section "Ability to affect the speed of reactions when driving vehicles or other mechanisms"). If there are complaints about vision, such patients should be referred to an ophthalmologist and the issue of drug withdrawal should be considered.
Musculoskeletal and connective tissue disorders
Against the background of the use of Roaccutane®
possible pain in muscles and joints, increased serum creatine phosphokinase, especially during intense physical exertion (see section "Adverse reactions").
Several years after the use of Roaccutane® for the treatment of dyskeratosis at very high doses, bone changes developed, including premature closure of the epiphyseal growth plates, hyperostosis, and calcification of ligaments and tendons. The doses, duration of treatment, and total cumulative dose in these patients generally exceeded those recommended for the treatment of acne.
Benign intracranial hypertension
Cases of benign intracranial hypertension have been described, some of which were caused by concomitant use with tetracyclines (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions"). Symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and swelling of the optic nerve head. Patients who develop benign intracranial hypertension should immediately discontinue the drug.
Hepatobiliary disorders
It is recommended to monitor liver enzymes before treatment, 1 month after its initiation, and then every 3 months, unless there is a clinical indication for more frequent monitoring. Transient and reversible increases in liver transaminase levels have been observed, in most cases within the normal range, which returned to baseline during treatment. If transaminase levels exceed the normal range, the dose of the drug should be reduced or discontinued.
Kidney failure
Renal impairment or renal failure does not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin can be administered to patients with renal failure. However, it is recommended to start with a low dose and titrate it to the maximum tolerated dose (see section "Method of administration and dosage").
Lipid metabolism
Fasting serum lipid levels should be measured (prior to treatment, 1 month after initiation, then every 3 months unless clinically indicated for more frequent monitoring). Elevated serum lipids usually resolve after dose reduction or discontinuation and with diet. Isotretinoin has been associated with increases in triglycerides. Isotretinoin should be discontinued in the event of uncontrolled hyperlipidemia or symptoms of pancreatitis. Elevated triglycerides above 800 mg/dL or 9 mmol/L may be associated with the development of acute pancreatitis, which may be fatal.
Gastrointestinal disorders
Inflammatory bowel disease (including regional ileitis) may develop during treatment with isotretinoin. Patients with severe (hemorrhagic) diarrhea should immediately discontinue the drug.
Fructose intolerance
Roaccutane® contains sorbitol. Patients with hereditary fructose intolerance should not take this medicine.
High-risk groups
Patients with diabetes mellitus, obesity, alcoholism or lipid metabolism disorders may require more frequent monitoring of serum glucose and/or lipids during treatment with isotretinoin. Increased fasting blood sugar and new cases of diabetes mellitus have been reported during treatment with isotretinoin.
Use during pregnancy or breastfeeding
Fetal malformations associated with isotretinoin include central nervous system abnormalities (hydrocephalus, cerebellar malformations/abnormalities, microcephaly), facial malformations, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canal), eye malformations (microphthalmia), cardiac and vascular anomalies (conotruncal heart defects such as tetralogy of Fallot, transposition of the great vessels, septal defects), thymic and parathyroid gland abnormalities. In addition, the risk of spontaneous abortions is increased.
If pregnancy occurs in a woman receiving isotretinoin treatment, therapy should be discontinued and a physician specializing and experienced in teratology should be consulted for evaluation and advice.
Breast-feeding.
Due to the high lipophilicity of isotretinoin, there is a high probability that it will be excreted in breast milk. Due to the possible side effects in the child associated with the action of the drug through breast milk, the use of isotretinoin is contraindicated in women during breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
During treatment and, in rare cases, after it, some patients have experienced a decrease in twilight vision (see sections "Adverse reactions", "Special instructions for use"). Since in some individuals these phenomena occurred suddenly, patients should be informed of the possibility of this problem and warned about the need to be careful when driving vehicles or operating other mechanisms.
Very rarely, drowsiness, dizziness, and visual disturbances have been reported. Patients should be advised that if these symptoms occur, they should not drive, operate machinery, or engage in other activities that could put themselves or others at risk.
Method of administration and doses
Standard dosage regimen.
Isotretinoin treatment should only be prescribed and administered by a physician who is experienced in the use of systemic retinoids for the treatment of severe acne and is fully aware of the risks of retinoid therapy and the requirements for monitoring patient conditions.
Capsules are taken with meals 1-2 times a day.
Adults (including adolescents and the elderly). Treatment should be initiated at a dose of 0.5 mg/kg/day. The therapeutic response to isotretinoin and some adverse reactions are dose-dependent and vary from patient to patient. Therefore, individual dose adjustment is necessary during treatment. In most patients, the dose ranges from 0.5 to 1 mg/kg/day.
Long-term remission and relapse rate are more related to the total dose administered than to the duration of treatment or daily dose. It has been shown that no additional benefit should be expected from a course dose above 120-150 mg/kg. The duration of therapy depends on the daily dose. A course of treatment of 16-24 weeks is usually sufficient to achieve remission.
In most patients, acne completely disappears after a single course of treatment. In case of severe relapse, a second course of treatment with Roaccutane® should be carried out at the same daily and course dose as the first. Since improvement may occur within 8 weeks after the end of treatment, a second course should be prescribed no earlier than the end of this period.
Dosage in special cases.
Patients with severe renal impairment: In patients with severe renal impairment, treatment should be initiated at a lower dose (e.g. 10 mg/day) and then increased to 1 mg/kg/day or to the maximum tolerated dose.
Children: Isotretinoin is contraindicated for the treatment of acne in prepubertal patients and in patients under 12 years of age due to a lack of data on efficacy and safety.
Patients with intolerance. Patients who develop severe intolerance to the recommended dose may be continued at a lower dose. In this case, the duration of therapy will be longer and the risk of relapse is higher. In order to achieve the maximum possible efficacy, the highest tolerated dose should be used.
Children
The use of Roaccutane® in children under 12 years of age has not been studied, therefore the drug should not be prescribed to children in this age category.
Overdose
Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretinoin is low, signs of hypervitaminosis A may occur in the event of accidental overdose. Symptoms of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and itching. Symptoms of accidental or intentional overdose of isotretinoin are likely to be similar. These symptoms are reversible and resolve without the need for treatment.
Adverse reactions
Some side effects of isotretinoin are dose-related. Adverse reactions are usually reversible after dose adjustment or discontinuation of the drug, but some may persist after discontinuation of treatment. The most commonly reported symptoms with isotretinoin are dryness of the skin, mucous membranes, including the lips (cheilitis), nose (epistaxis), and eyes (conjunctivitis).
Infections: very rarely common – gram-positive bacterial infections of the skin and mucous membranes.
Blood and lymphatic system disorders: very common - anemia, increased ESR, thrombocytopenia, thrombocytosis; common - neutropenia; very rare - lymphadenopathy.
Immune system disorders: rarely - allergic skin reactions, anaphylactic reactions, hypersensitivity reactions.
Metabolic disorders: very rarely common – diabetes mellitus, hyperuricemia.
Psychiatric disorders: rare – depression, increased depression, tendency to aggression, anxiety, mood changes; very rare – behavioral disorders, psychotic disorders, suicide attempts, suicide.
Nervous system disorders: common - headache; very rare - benign intracranial hypertension, convulsions, drowsiness, dizziness.
Eye disorders: very common - blepharitis, conjunctivitis, dry eyes, eye irritation; very rare - blurred vision, cataract, color vision impairment, contact lens intolerance, corneal opacity, decreased twilight vision, keratitis, optic nerve head swelling (as a manifestation of benign intracranial hypertension), photophobia, visual impairment.
Hearing and labyrinth disorders: very rare – hearing impairment.
Vascular disorders: very rare - vasculitis (e.g. Wegener's granulomatosis, allergic vasculitis).
Respiratory, thoracic and mediastinal disorders: common - epistaxis, dry nose, nasopharyngitis; very rare - bronchospasm (especially in patients with asthma), dysphonia.
Gastrointestinal disorders:
Very rare: colitis, ileitis, dry throat, gastrointestinal bleeding, hemorrhagic diarrhea, inflammatory bowel disease, nausea, pancreatitis. Cases of severe diarrhea have also been reported (see section "Special warnings and precautions for use").
Hepatobiliary disorders:
very common - increased transaminases (see section "Special warnings and precautions for use"); very rare - hepatitis.
Skin and subcutaneous tissue disorders: very common - cheilitis, dermatitis, dry skin, localized peeling, itching, erythematous rash, skin trauma (risk of injury from friction); rare - alopecia; very rare - acne fulminant, acne exacerbation (acne hyperemia), erythema (face), exanthema, hair disorders, hirsutism, onychodystrophy, paronychia, photosensitivity, pyogenic granuloma, skin hyperpigmentation, increased sweating; frequency unknown* - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Bone, muscle and connective tissue disorders: very common - arthralgia, myalgia, back pain (especially in children and adolescents); very rare - arthritis, calcification (calcification of ligaments and tendons), premature closure of epiphyseal growth plates, exostosis, hyperostosis, decreased bone density, tendinitis.
Kidney and urinary system disorders: very rare – glomerulonephritis.
General disorders: very rarely common – granulation tissue (increased formation), fatigue.
Laboratory parameters: very common - hypertriglyceridemia, decreased high-density lipoprotein levels; common - hypercholesterolemia, hyperglycemia, hematuria, proteinuria; very rare - increased CPK in the blood.
*- frequency cannot be estimated based on available data.
Adverse reactions observed in the post-marketing period
Serious cases of rhabdomyolysis have been reported, often leading to hospitalization and some fatal, particularly in those engaged in vigorous physical activity.
Expiration date
3 years.
Storage conditions
Keep out of reach of children.
Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture and light.
Packaging
10 capsules of 10 mg or 20 mg in PVC/PE/PVDC/aluminium foil or PVC/PVDC/aluminium foil blisters. 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
F. Hoffmann-La Roche Ltd, Switzerland
Location of the manufacturer and its business address.
Grenzacherstrasse 124, CH-4070 Basel, Switzerland
