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Roaccutane 0.02 N30
Roaccutane 0.02 N30
Product Code: roaccutane-0.02-n30 "03 ГНЦЛС"

Roaccutane 0.02 N30

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$93.50
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Composition
One 20 mg capsule contains:

active ingredient: isotretinoin - 20 mg;

auxiliary substances: soy bean oil - 215.84 mg, beeswax yellow - 15.36 mg, hydrogenated soy bean oil - 15.36 mg, partially hydrogenated soy bean oil - 61.44 mg;

capsule shell: glycerol 85% - 49.835 mg, gelatin - 120.66 mg, Carion 83 (hydrolyzed potato starch, mannitol, sorbitol) - 12.86 mg, iron oxide red dye (E172) - 0.145 mg, titanium dioxide (E171) - 1.97 mg;

ink for the capsule inscription: shellac, iron oxide black dye (E172); ready-to-use Opacode Black S-1-27794 ink may be used.
Pharmacological action

Pharmacotherapeutic group
Acne treatment

ATX code [D10BA01].

Pharmacological action
Retinoid for systemic treatment of acne

Isotretinoin is the stereoisomer of fully transretinoic acid (tretinoin).
The precise mechanism of action of Roaccutan® is not yet understood, but it is established that the improvement of the clinical picture of severe acne is associated with the suppression of sebaceous gland activity and histologically confirmed reduction in the size of the sebaceous gland. Furthermore, the anti-inflammatory effect of isotretinoin on the skin has been proven.

Hyperkeratosis of hair follicle epithelial cells and sebaceous glands leads to sloughing of root cells into the gland duct and clogging of the latter with keratin and excess sebum. This is followed by the formation of a comedon and, in some cases, an inflammatory process.

Roaccutane® inhibits the proliferation of sebocytes and acts on acne, restoring the normal process of cell differentiation. Sebum is the main substrate for Propionibacterium acnes growth, therefore, reduction of sebum formation suppresses bacterial colonisation of the duct.

Pharmacokinetics

As the kinetics of isotretinoin and its metabolites are linear, plasma concentrations during therapy can be predicted from a single dose. This property of the drug also indicates that it does not affect the activity of hepatic enzymes involved in drug metabolism.

Absorption

Absorption of isotretinoin from the gastrointestinal tract is variable. The absolute bioavailability of isotretinoin has not been determined, as there is no formulation for intravenous use in humans. However, extrapolation of data obtained in an experiment in dogs suggests a rather low and variable systemic bioavailability.

In acne patients, maximum plasma concentrations (Smax) in equilibrium after fasting administration of 80 mg of isotretinoin were 310 ng/ml (range 188-473 ng/ml) and were reached after 2-4 hours. Plasma concentrations of isotretinoin are approximately 1.7 times higher than blood concentrations, due to poor isotretinoin penetration into erythrocytes.

Ingestion of isotretinoin with food increases bioavailability by 2 times compared to an empty stomach.

Distribution

Isotretinoin binds strongly (99.9%) with plasma proteins, mainly with albumins, so that in wide range of therapeutic concentrations free (pharmacologically active) fraction contains less than 0.1% of total amount.
The volume of distribution of isotretinoin in humans was not determined, as there is no dosage form for intravenous administration.

Blood equilibrium concentrations (Cmin ss) of isotretinoin in patients with severe acne, treated with 40 mg twice daily, ranged from 120 to 200 ng/ml.
The 4-oxo isotretinoin concentrations in these patients were 2.5 times higher than isotretinoin concentrations. There is insufficient data on the tissue penetration of isotretinoin in humans. Isotretinoin concentrations in the epidermis are half those in serum.

Metabolism

After oral administration three main metabolites are detected in plasma: 4-oxo-isotretinoin, tretinoin (fully transretinoic acid) and 4-oxo-retinoin. The main metabolite is 4-oxo-isotretinoin, whose plasma concentrations in equilibrium are 2.5 times higher than those of the parent drug. Less significant metabolites have also been found, including glucuronides, but the structure of not all metabolites has been established.

Isotretinoin metabolites have biological activity, confirmed in several laboratory tests. Thus, the clinical effects of the drug in patients could be the result of the pharmacological activity of isotretinoin and its metabolites.

As in vivo isotretinoin and tretinoin (fully transretinoic acid) are reversibly converted to each other, the metabolism of tretinoin is related to that of isotretinoin. 20-30% of the dose of isotretinoin is metabolised by isomerisation.

Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans.
In vitro metabolism studies have shown that several enzymes of the cytochrome P450 system (CYP) are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. None of the isoforms appears to play a dominant role. Roaccutane® and its metabolites have no significant effect on the activity of CYP enzymes.

Excretion

After oral administration of radioactively labelled isotretinoin, approximately equal amounts are detected in urine and faeces. The half-life of the terminal phase for the unchanged product in acne patients is on average 19 hours. The half-life of 4-oxo-isotretinoin appears to be longer, averaging 29 hours.

Isotretinoin belongs to natural (physiological) retinoids. Endogenous concentrations of retinoids are restored approximately 2 weeks after termination of taking Roaccutan®.

Pharmacokinetics in special clinical cases

Because isotretinoin is contraindicated in patients with hepatic impairment, there are limited data about its pharmacokinetics in this group of patients.
Renal failure does not influence pharmacokinetics of isotretinoin.

Indications

Acne that does not respond to other therapies Severe acne (cystic nodules, conglobate acne or acne with risk of scarring).

Use during pregnancy and lactation
Isotretinoin is a medicine with strong teratogenic effects. If pregnancy occurs while a woman is taking oral isotretinoin (in any dose and even for a short time), there is a very high risk of birth of a child with malformations.

Roaccutane® is contraindicated in women of childbearing age unless the woman fulfils all of the following criteria

- she must have severe acne that is resistant to conventional treatments;
- She must accurately understand and follow the doctor's instructions;
- She must have been informed by her doctor about the risk of pregnancy during her treatment with

Roaccutane® within one month of treatment and urgent advice if pregnancy is suspected;
- she must be warned about the possible ineffectiveness of contraception;
- she must confirm that she understands the precautionary measures;
- she must understand the need for and continue to use effective contraception for one month before, during and one month after treatment with Roaccutane® (see section on Interaction with other medicines); two different contraceptive methods, including barrier contraception, should preferably be used simultaneously;
- she must have had a negative valid pregnancy test within 11 days before starting treatment; a pregnancy test is highly recommended monthly during treatment and 5 weeks after the end of treatment;
- she should begin treatment with Roaccutane® only on the 2nd or 3rd day of her next normal menstrual cycle;
- she should be aware of the need for an obligatory monthly visit to her doctor;
- if she is treated for a recurrence of the disease, she should always use the same effective contraceptive methods for one month before starting treatment with Roaccutane®, during treatment and for one month after treatment ends, and undergo the same reliable pregnancy test;
- she must fully understand the need for precautionary measures and confirm her understanding and willingness to use reliable contraceptive methods as explained to her by her doctor.

The use of contraception according to the above instructions during treatment with isotretinoin should be recommended even for women who do not normally use contraception due to infertility (except for patients who have had a hysterectomy), amenorrhoea or who report that they are not sexually active.

The doctor must be sure that:
- The patient has a severe form of acne (cystic nodules, conglobate acne or acne with risk of scarring); acne that is not amenable to other therapies;
- a negative valid pregnancy test is obtained before starting treatment, during treatment and 5 weeks after treatment has ended; the dates and results of the pregnancy test should be documented;
- the patient has used at least 1, preferably 2, effective methods of contraception, including a barrier method, for one month before starting Roaccutane® , during treatment and for one month after treatment has ended;
- the patient is able to understand and comply with all the above mentioned contraceptive requirements;
- the patient complies with all the above requirements.

Pregnancy test

According to current practice, a pregnancy test with a minimum sensitivity of 25 mU/mL should be performed on the first 3 days of the menstrual cycle:

Before the start of therapy:
The result and date of the initial pregnancy test should be recorded by the physician to exclude possible pregnancy before the start of contraception. In patients with irregular periods, the timing of the pregnancy test depends on sexual activity and should be performed 3 weeks after unprotected intercourse. Your doctor must inform you about the contraceptive method.
The pregnancy test is performed on the day Roaccutan® is prescribed or 3 days before the patient's visit. The specialist should record the results of the test. The drug may only be administered to patients who have received effective contraception for at least 1 month before starting treatment with Roaccutane®.

During therapy:
The patient must see her doctor every 28 days. The need for monthly pregnancy tests is determined according to local practice and taking into account sexual activity, previous menstrual irregularities. If indicated, a pregnancy test is performed on the day of the visit or three days before the visit and the results of the test must be recorded.
End of treatment:
A test is performed 5 weeks after the end of therapy to rule out pregnancy.
A prescription for Roaccutane® can only be given for 30 days, continuation of therapy requires a new prescription by the doctor. It is recommended that the pregnancy test, prescription and dispensing be done on the same day.

Roaccutan® should be dispensed at the pharmacy only within 7 days from the date of prescription.

Full information about teratogenic risks and strict adherence to measures to prevent pregnancy must be given to both men and women. Male patients

Existing data suggest that in women, exposure from semen and seminal fluid of men taking Roaccutan® is not sufficient to cause teratogenic effects of Roaccutan®.

Men should exclude the possibility of other persons, especially women, taking the drug.
If, despite the precautions taken, pregnancy occurs during treatment with Roaccutan® or within one month after its termination, there is a high risk of very severe fetal malformations (especially of the central nervous system, heart and large blood vessels). There is also an increased risk of spontaneous miscarriage.

If pregnancy occurs, treatment with Roaccutan® should be discontinued. It should be discussed with a teratology physician.

Severe congenital malformations of the human fetus associated with administration of Roaccutane® have been documented, including hydrocephaly, microcephaly, cerebellar malformations, external ear anomalies (microtia, anomalies of the external ear (microtia, narrowing or absence of the external auditory canal), microphthalmia, cardiovascular anomalies (tetrada fallo, transposition of great vessels, septal defects), facial malformations (cleft palate), thymus gland, parathyroid gland pathology.

Because isotretinoin is highly lipophilic, it is very likely to enter breast milk. Due to possible side effects, Roaccutane® should not be administered to breastfeeding mothers.
Contraindications

Pregnancy, lactation, hepatic insufficiency, hypervitaminosis A, marked hyperlipidemia, concomitant therapy with tetracyclines.

Hypersensitivity to the drug or its components.

Childhood under 12 years of age.
Side effects

Most of the side effects of Roaccutane are dose-related. Generally, when prescribed the recommended doses, the benefit/risk ratio is acceptable to the patient, taking into account the severity of the disease. The side effects are usually reversible after adjusting the dose or withdrawing the drug, but some may persist after stopping treatment.

Symptoms associated with hypervitamin A: dry skin, mucous membranes, including lips (cheilitis), nasal cavity (bleeding), pharynx (hoarseness), eyes (conjunctivitis, reversible corneal clouding and contact lens intolerance).

Skin and skin appendages: rash, itching, facial erythema/dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased granulation growth, permanent thinning of hair, reversible hair loss, fulminant acne, hirsutism, hyperpigmentation, photosensitivity, photoallergy, mild skin injury. At the start of treatment, acne flare-ups may occur, persisting for several weeks.

Musculoskeletal system: muscle pain with or without increase in serum CPK levels, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, other bone changes, tendinitis.

Central nervous system and mental system: behavioural disorders, depression, headache, increased intracranial pressure ("pseudotumour of the brain": headache, nausea, vomiting, visual disturbances, oedema of the optic nerve), seizures.

Sensory organs: isolated cases of visual acuity disorders, photophobia, dark adaptation disorders (decreased acuity of crepuscular vision), rarely - colour perception disorders (resolving after drug withdrawal), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, optic nerve edema (as manifestation of intracranial hypertension); hearing disorders at certain sound frequencies.

 Gastrointestinal tract: nausea, diarrhoea, inflammatory bowel disease (colitis, ileitis), bleeding; pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg/dL). Rare cases of fatal pancreatitis have been described.

Transient and reversible increases in hepatic transaminases, isolated cases of hepatitis. In many of these cases the changes were within normal limits and returned to baseline values during treatment, but in some situations it was necessary to reduce the dose or cancel Roaccutane.

Respiratory system: rare bronchospasm (more common in patients with a history of bronchial asthma).

Blood system: anemia, decreased hematocrit, leukopenia, neutropenia, increased or decreased platelet count, accelerated sedimentation rate.

Laboratory parameters: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, decreased levels of high-density lipoproteins, rarely - hyperglycemia. Cases of newly diagnosed diabetes mellitus have been reported during administration of Roaccutane. Individual cases of increased serum CPK activity have been described in some patients, especially those engaged in strenuous physical activity.

Immune system: local or systemic infections caused by Gram-positive pathogens (Staphylococcus aureus).

Other: lymphadenopathy, hematuria, proteinuria, vasculitis (Wegener's granulomatosis, allergic vasculitis), systemic hypersensitivity reactions, glomerulonephritis.
Interaction .

Because of possible worsening of symptoms of hypervitaminosis A, concomitant administration of Roaccutane and vitamin A should be avoided.
As tetracyclines may also cause increased intracranial pressure, their use in combination with Roaccutane is contraindicated.

Isotretinoin may weaken the efficacy of progesterone preparations, therefore contraceptives containing low doses of progesterone should not be used.

Combined use with topical keratolytic or exfoliative agents for the treatment of acne is contraindicated due to possible increased local irritation.
How to take, course of treatment and dosage

Standard dosage regimen

Orally, with meals once or twice a day.

The therapeutic efficacy of Roaccutane and its side effects depend on the dose and vary from patient to patient. This dictates that the dose should be adjusted individually during treatment.

Roaccutane treatment should be started with a dose of 0.5 mg/kg per day. In most patients the dose ranges from 0.5 to 1.0 mg/kg body weight per day. Patients with very severe forms of the disease or with torso acne may require higher daily doses, up to 2.0 mg/kg.

It has been proven that remission rates and relapse prevention are optimal when using a course dose of 120-150 mg/kg (per course of treatment), so the duration of therapy in specific patients varies with the daily dose. Complete remission of acne is often achieved within 16-24 weeks of treatment. In patients who do not tolerate the recommended dose very well, treatment can be continued at a lower dose, but for longer periods.

In most patients, acne disappears completely after a single course of treatment. If there is a clear relapse, a second course of treatment with Roaccutane at the same daily and course dose as the first is indicated. As improvement may continue up to 8 weeks after withdrawal, a second course should not be prescribed before the end of this period.

Dosage in special cases

In patients with severe renal failure, treatment should be started with a lower dose (e.g. 10 mg/day) and further increased to 1 mg/kg/day or the maximum tolerated dose.

Overdose

An overdose may cause signs of hypervitaminosis A.

Gastric lavage may be necessary in the first few hours after an overdose.
Special directions

Roaccutane should only be prescribed by a physician, preferably a dermatologist, experienced in the use of systemic retinoids and aware of the risk of teratogenicity. Both female and male patients should be given a copy of the patient information leaflet.
In order to avoid accidental exposure of other people to the drug, donor blood should not be taken from patients who are receiving or have received Roaccutane shortly before (1 month).

It is recommended that liver function and liver enzymes be monitored before treatment, 1 month after initiation and then every 3 months or as indicated. Transient and reversible increases in liver transaminases have been reported, in most cases within normal limits. If liver transaminases exceed normal levels, the dose should be reduced or the drug should be discontinued.
Serum lipid levels should also be determined on an empty stomach before treatment, 1 month after initiation, and then every 3 months or as indicated. Lipid concentrations usually normalise after dose reduction or withdrawal of the drug, and with dietary compliance. Clinically significant increases in triglyceride levels should be controlled as elevations above 800 mg/dl, or 9 mmol/l, may be accompanied by the development of acute pancreatitis, possibly fatal. In cases of persistent hypertriglyceridemia or symptoms of pancreatitis, Roaccutane should be discontinued.

Rarely, depression, psychotic symptoms and very rarely suicide attempts have been described in patients treated with Roaccutane. Although their causal relationship to the use of the drug has not been established, special caution should be exercised in patients with a history of depression and all patients should be monitored for depression during treatment with the drug, referring them to an appropriate specialist if necessary. However, withdrawal of Roaccutane may not lead to disappearance of symptoms and further monitoring and treatment by a specialist may be required.

In rare cases, an acne flare-up is noted at the start of therapy, which subsides within 7-10 days without adjustment of the drug dose.
Several years after the use of Roaccutane for the treatment of dyskeratoses at a total dose and duration of therapy higher than recommended for acne therapy, bone changes developed, including premature closure of epiphyseal growth zones, hyperostosis, calcification of ligaments and tendons. Therefore, when prescribing the drug to any patient, the possible benefit/risk ratio should be carefully assessed beforehand.

Patients receiving Roaccutane are advised to use a moisturising ointment or body cream or lip balm to reduce skin and mucosal dryness at the start of therapy.

Cases of severe skin reactions, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, have been described during post-marketing monitoring of Roaccutane. These effects can be serious and may lead to disability, life-threatening conditions, hospitalisation or fatal outcome. Patients receiving Roaccutane should be closely monitored to detect severe skin reactions and, if necessary, to decide whether to withdraw the drug.

During administration of Roaccutane, muscle and joint pain, increased serum creatinine phosphokinase may occur, which may be accompanied by decreased tolerance to strenuous physical activity.

Deep chemical dermoabrasion and laser treatment should be avoided in patients receiving Roaccutane and for 5-6 months after treatment termination because of the possibility of increased scarring in atypical sites and the occurrence of hyper- and hypopigmentation. Waxing should not be performed during and for 6 months after treatment with Roaccutane because of the risk of epidermal detachment, scarring and dermatitis.

As some patients may have decreased visual acuity at night, which sometimes persists after treatment has ended, patients should be informed about the possibility of this condition, advising them to be cautious when driving at night. Visual acuity should be monitored closely.

Overdose

An overdose may cause signs of hypervitaminosis A.

Gastric lavage may be necessary in the first few hours after an overdose.
Special directions

Roaccutane should only be prescribed by a physician, preferably a dermatologist, experienced in the use of systemic retinoids and aware of the risk of teratogenicity. Both female and male patients should be given a copy of the patient information leaflet.
In order to avoid accidental exposure of other people to the drug, donor blood should not be taken from patients who are receiving or have received Roaccutane shortly before (1 month).

It is recommended that liver function and liver enzymes be monitored before treatment, 1 month after initiation and then every 3 months or as indicated. Transient and reversible increases in liver transaminases have been reported, in most cases within normal limits. If liver transaminases exceed normal levels, the dose should be reduced or the drug should be discontinued.
Serum lipid levels should also be determined on an empty stomach before treatment, 1 month after initiation, and then every 3 months or as indicated. Lipid concentrations usually normalise after dose reduction or withdrawal of the drug, and with dietary compliance. Clinically significant increases in triglyceride levels should be controlled as elevations above 800 mg/dl, or 9 mmol/l, may be accompanied by the development of acute pancreatitis, possibly fatal. In cases of persistent hypertriglyceridemia or symptoms of pancreatitis, Roaccutane should be discontinued.

Rarely, depression, psychotic symptoms and very rarely suicide attempts have been described in patients treated with Roaccutane. Although their causal relationship to the use of the drug has not been established, special caution should be exercised in patients with a history of depression and all patients should be monitored for depression during treatment with the drug, referring them to an appropriate specialist if necessary. However, withdrawal of Roaccutane may not lead to disappearance of symptoms and further monitoring and treatment by a specialist may be required.

In rare cases, an acne flare-up is noted at the start of therapy, which subsides within 7-10 days without adjustment of the drug dose.
Several years after the use of Roaccutane for the treatment of dyskeratoses at a total dose and duration of therapy higher than recommended for acne therapy, bone changes developed, including premature closure of epiphyseal growth zones, hyperostosis, calcification of ligaments and tendons. Therefore, when prescribing the drug to any patient, the possible benefit/risk ratio should be carefully assessed beforehand.

Patients receiving Roaccutane are advised to use a moisturising ointment or body cream or lip balm to reduce skin and mucosal dryness at the start of therapy.

Cases of severe skin reactions, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, have been described during post-marketing monitoring of Roaccutane. These effects can be serious and may lead to disability, life-threatening conditions, hospitalisation or fatal outcome. Patients receiving Roaccutane should be closely monitored to detect severe skin reactions and, if necessary, to decide whether to withdraw the drug.

During administration of Roaccutane, muscle and joint pain, increased serum creatinine phosphokinase may occur, which may be accompanied by decreased tolerance to strenuous physical activity.

Deep chemical dermoabrasion and laser treatment should be avoided in patients receiving Roaccutane and for 5-6 months after treatment termination because of the possibility of increased scarring in atypical sites and the occurrence of hyper- and hypopigmentation. Waxing should not be performed during and for 6 months after treatment with Roaccutane because of the risk of epidermal detachment, scarring and dermatitis.

As some patients may have decreased visual acuity at night, which sometimes persists after treatment has ended, patients should be informed about the possibility of this condition, advising them to be cautious when driving at night. Visual acuity should be monitored closely.

Conjunctival dryness, corneal clouding, worsening of night vision and keratitis usually go away after withdrawal. If the mucous membrane is dry, moisturising ointments or artificial tears may be applied. Patients with dry conjunctiva should be monitored for possible keratitis. Patients with visual complaints should be referred to an ophthalmologist and consideration should be given as to whether Roaccutane should be withdrawn. If contact lenses are intolerant, spectacles should be worn during therapy.

Exposure to sunlight and UV rays should be limited. If necessary, a sunscreen with a high SPF of at least 15 should be used.

Rare cases of benign intracranial hypertension ("pseudotumour of the brain") have been reported, also when combined with tetracyclines. Roaccutane should be stopped immediately in these patients.

Inflammatory bowel disease may occur during therapy with Roaccutane. In patients with severe haemorrhagic diarrhoea, Roaccutane should be stopped immediately.

Rare cases of anaphylactic reactions have been described that occurred only after previous external application of retinoids. Severe allergic reactions necessitate withdrawal of the drug and close monitoring of the patient.

Patients in the high-risk group (with diabetes mellitus, obesity, chronic alcoholism or fat metabolism disorders) may require more frequent laboratory monitoring of glucose and lipid levels during treatment with Roaccutane.

In the presence or suspicion of diabetes, more frequent glycaemic tests are recommended.

Form of production

Capsules .

Storage conditions
Store at a temperature not exceeding 25°C, protected from light and moisture.

Keep out of reach of children.

Shelf life
3 years.
Active substance
Isotretinoin
Conditions for dispensing from pharmacies
Prescription
Pharmaceutical form
capsules
Indications
Severe acne

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