Roaccutane - instructions for use, dose, side effects, contraindications

Excipients: soybean oil - 107.92 mg, beeswax yellow - 7.68 mg, soya beans hydrogenated oil - 7.68 mg, soya beans partially hydrogenated oil - 30.72 mg;

shell capsules: glycerol 85% - 31.275 mg, gelatin - 75.64 mg, Carion 83 (potato hydrolyzed starch, mannitol, sorbitol) - 8.065 mg, iron dye red oxide (E172) - 0.185 mg, titanium dioxide (E171) -1.185 mg;

ink for applying the inscription on the capsule: shellac, iron dye oxide black (E172); it is allowed to use ready-made ink Opacode Black S-1-17823.

One capsule of 20 mg contains:

active substance: isotretinoin - 20 mg;

Excipients: soybean oil - 215.84 mg, beeswax yellow - 15.36 mg, soya beans, hydrogenated oil - 15.36 mg, soya beans, partially hydrogenated oil - 61.44 mg;

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

ink for applying the inscription on the capsule: shellac, iron dye oxide black (E172); it is allowed to use ready-made ink Opacode Black S-l-17823.

Description:

Capsules 10mg: oval capsules, brownish-red, opaque; on the surface of the capsule inscription in black ink "ROA 10 ", the contents of the capsule - a homogeneous suspension from yellow to dark yellow.

Capsules 20 mg: oval capsules, one half brownish-red, opaque, the other half white, opaque; on the surface of the capsule inscription in black ink "ROA 20 ", the contents of the capsule - a homogeneous suspension from yellow to dark yellow color.

Pharmacotherapeutic group:A remedy for acne.

ATX: & nbsp

D.10.B.A.01 Isotretinoin

Pharmacodynamics:

Retinoid for systemic therapy of acne

Isotretinoin is a stereoisomer of fully trans-retinoic acid (tretinoin). The exact mechanism of action of the drug Roaccutane® has not yet been clarified,that improvement of the clinical picture of severe forms of acne is associated with suppression of sebaceous gland activity and histologically confirmed decrease in their size. In addition, the anti-inflammatory effect of isotretinoin on the skin has been proven.

Hyperkeratosis of epithelial cells of hair follicles and sebaceous glands leads to shedding of corneocytes into the duct and gland plugging last keratin and excess sebaceous secretion. This is followed by the formation of a comedon and, in some cases, the attachment of an inflammatory process. Roaccutane® suppresses the proliferation of sebocytes and acts on acne, restoring the normal process of cell differentiation. Skin fat - the main substrate for growth Propionibacterium acnes, so reducing the formation of sebum suppresses the bacterial colonization of the duct.

Pharmacokinetics:

Since the kinetics of isotretinoin and its metabolites is linear, its plasma concentrations during therapy can be predicted on the basis of data obtained after a single dose. This property of the drug also suggests that it does not affect the activity of hepatic enzymes involved in the metabolism of drugs. Suction

Absorption of isotretinoin from the gastrointestinal tract fluctuates. Absolute bioavailability of isotretinoin was not determined, since there are no forms of drug release for intravenous use in humans. However, extrapolation of the data obtained in the experiment on dogs suggests a rather low and variable systemic bioavailability. In patients with acne, the maximum plasma concentrations (C_Max) in the equilibrium state after administration of 80 mg of fasting isotretinoin were 310 ng / ml (range 188-473 ng / ml) and were achieved after 2-4 hours. The concentration of isotretinoin in the plasma is about 1.7 times higher than the concentration in the blood, due to the poor penetration of isotretinoin into erythrocytes.

The intake of isotretinoin with food increases bioavailability by 2 times compared with fasting.

Distribution

Isotretinoin binds to a high degree (99.9%) with plasma proteins, mainly with albumins, so that in a wide range of therapeutic concentrations, the content of the free (pharmacologically active) fraction of the drug is less than 0.1% of its total.

The volume of isotretinoin distribution in humans has not been determined, since there is no dosage form for intravenous administration.

Equilibrium concentrations of isotretinoin in the blood (C_mines_ss) In patients with severe acne, taking 40 mg of the drug twice a day, ranged from 120 to 200 ng / ml.

The concentrations of 4-oxo-isotretinoin in these patients were 2.5 times higher than that of isotretinoin. Data on the penetration of isotretinoin in human tissue is not enough. The concentration of isotretinoin in the epidermis is two times lower than in serum.

Metabolism

After ingestion, three main metabolites are detected in the plasma: 4-oxo- isotretinoin, tretinoin (fully trans-retinoic acid) and 4-oxo-retinoin. The main metabolite is 4-oxo-isotretinoin, the plasma concentrations of which in the equilibrium state are 2.5 times higher than the concentrations of the parent drug. There are also less significant metabolites including also glucuronides, but not all metabolites are established.

Metabolites of isotretinoin have biological activity, confirmed in several laboratory tests.Thus, the clinical effects of the drug in patients can be the result of the pharmacological activity of isotretinoin and its metabolites. Because the in vivo isotretinoin and tretinoin (completely trans-retinoic acid) reversibly convert into each other, the metabolism of tretinoin is associated with the metabolism of isotretinoin. 20-30% of the dose of isotretinoin is metabolized by isomerization. In the pharmacokinetics of isotretinoin in humans, an important role may be played by enterohepatic circulation.

Metabolic Studies in vitro showed that in the conversion of isotretinoin to 4-oxo- isotretinoin and tretinoin Several enzymes of the cytochrome P450 system are involved (CYP):. Apparently, none of the isoforms plays the dominant role. Roaccutane® and its metabolites have no significant effect on the activity of the enzymes of the system CYP.

Excretion

After ingestion of radiolabeled isotretinoin in urine and feces, approximately the same amount is found. The half-life of the terminal phase for the unchanged drug in patients with acne is an average of 19 hours. The half-life of the terminal phase for 4-oxo-isotretinoin appears to be larger and equals an average of 29 hours.

Isotretinoin refers to natural (physiological) retinoids. Endogenous concentrations of retinoids are restored approximately 2 weeks after the end of the administration of Roaccutane®.

Pharmacokinetics in special clinical cases

Because the isotretinoin is contraindicated in cases of liver dysfunction, pharmacokinetics of the drug in this group of patients are limited.

Renal insufficiency does not affect the pharmacokinetics of isotretinoin.

Indications:

Heavy forms of acne (nodular-cystic, conglobate acne or acne with the risk of scar formation).

Acne, not amenable to other types of therapy.

Contraindications:

Pregnancy, the period of breastfeeding (see "Pregnancy and the period of breastfeeding"), liver failure, hypervitaminosis A, severe hyperlipidemia, concomitant therapy with tetracyclines.

Hypersensitivity to the drug or its components (including soy). Children under 12 years.

Carefully:Depression in history, diabetes, obesity, lipid metabolism, alcoholism.

Pregnancy and lactation:

Pregnancy is an absolute contraindication for therapy with Roaccutane®.If pregnancy occurs, despite warnings, during treatment or within a month after the end of therapy, there is a very high risk of a child with severe developmental defects.

Isotretinoin is a drug with a strong teratogenic effect. If pregnancy occurs during the period when a woman orally takes isotretinoin (at any dose and even for a short time), there is a very high risk of a child with developmental defects.

Roaccutane® is contraindicated in women of childbearing age, unless the woman's condition meets all of the following criteria:

- she should have a severe form of acne, resistant to conventional methods of treatment;

- she must accurately understand and follow the doctor's instructions;

- she should be informed by the doctor about the danger of pregnancy in the course of treatment with Roaccutane® within one month after it and urgent consultation in case of suspected pregnancy;

- she should be warned about the possible ineffectiveness of contraceptives;

- she must confirm that she understands the nature of precautions;

- she must understand the need and continuously use effective methods of contraception within one month prior to treatment with Roaccutane®, during treatment and for a month after its termination (see "Interactions with Other Drugs"); It is desirable to use at the same time 2 different methods of contraception, including barrier;

- she should receive a negative result of a valid pregnancy test within 11 days before the drug is taken; a pregnancy test is strongly recommended to be performed monthly during treatment and 5 weeks after the end of therapy;

- she should begin treatment with Roaccutane ® only on the 2-3 day of the next normal menstrual cycle;

- she must understand the need for a compulsory visit to the doctor every month;

- when treating for a relapse of the disease, she must constantly use the same effective methods of contraception within one month prior to the beginning of treatment with Roaccutane®, during treatment and within a month after its completion, and also undergo the same reliable pregnancy test;

- she must fully understand the need for precautionary measures and confirm her understanding and desire to apply reliable methods of contraception, which the doctor explained to her.

The use of contraceptives in accordance with the above instructions during treatment with isotretinoin should be recommended even to women who usually do not use contraceptive methods due to infertility (except for patients who underwent a hysterectomy), amenorrhea, or who report that they do not have sex.

The doctor should be sure that:

- the patient has a severe form of acne (nodular-cystic, conglobate acne or acne with risk of scarring); acne, not amenable to other types of therapy;

- a negative result of a valid pregnancy test was obtained prior to taking the drug, during therapy and 5 weeks after the end of therapy; the dates and results of the pregnancy test must be documented;

- the patient uses at least 1, preferably 2 effective methods of contraception, including the barrier method, within one month prior to initiation of treatment with Roaccutane®, during treatment and for a month after its termination;

- the patient is able to understand and fulfill all of the above requirements for protection from pregnancy;

- the patient meets all of the above conditions.

Pregnancy test

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

Before the start of therapy:

- To exclude a possible pregnancy before the application of contraception, the result and the date of the initial pregnancy test must be recorded by the doctor. In patients with irregular menstruation, the timing of the pregnancy test depends on sexual activity, it should be performed 3 weeks after unprotected intercourse. The doctor should inform the patient about the methods of contraception.

- The pregnancy test is carried out on the day of administration of the drug Roaccutane® or 3 days before the patient's visit to the doctor. The specialist should register the test results. The drug can be prescribed only to patients receiving effective contraception at least 1 month before starting therapy with Roaccutane®.

During therapy:

- The patient must visit the doctor every 28 days. The need for monthly pregnancy testing is determined in accordance with local practice and taking into account the sexual activity preceding the menstrual cycle disorders. If there is evidence, a pregnancy test is conducted on the day of the visit or three days before the visit to the doctor, the test results must be recorded.

End of therapy:

- After 5 weeks after the end of therapy, a test is performed to exclude pregnancy.

The recipe for Roaccutane® for a woman capable of childbearing can be discharged only for 30 days of treatment, continuation of therapy requires a new prescription of the drug by a doctor. It is recommended that a pregnancy test, a prescription and preparation be conducted on the same day.

The delivery of Roaccutane® in a pharmacy should be performed only within 7 days of the prescription.

To help doctors, pharmacists and patients avoid the risk of exposure to Roaccutane® on the fetus, the manufacturer has created a "Pregnancy Protection Program" aimed at preventing the teratogenicity of the drug and emphasizing the absolutely mandatoryuse of reliable contraceptive measures by women of childbearing age. The program contains the following materials:

for doctors:

- a guide for a doctor on the prescription of Roaccutane® to women

- informed consent form for the patient

- form of registration of the drug for women for the patient:

- information brochure for the patient

- what you need to know about contraception

- for the pharmacist:

- guide for the pharmacist on the release of Roaccutane®.

Complete information on teratogenic risk and strict adherence to measures to prevent pregnancy should be provided to both men and women.

To male patients

Existing evidence suggests that in women the exposure of the drug from the semen and semen of men taking Roacutan® is not sufficient for the occurrence of teratogenic effects of Roaccutane®.

Men should be excluded from the possibility of taking the drug by other people, especially women.

If, despite the precautionary measures taken, during the treatment with the drug Roaccutane® or for a month after the termination of the pregnancy,there is a high risk of very severe fetal malformations (in particular, from the central nervous system, heart and large blood vessels). In addition, the risk of spontaneous miscarriages increases.

If pregnancy occurs, therapy with Roaccutane® is stopped. It should be discussed the expediency of its preservation with a doctor specializing in teratology. Documentary confirmed severe congenital malformations of the fetus in humans associated with the administration of Roaccutane®, including hydrocephalus, microcephaly,(microtia, narrowing or absence of external auditory canal), microphthalmia, cardiovascular anomalies (tetralogy of Fallot, transposition of the main vessels, defects of partitions), malformations of the face (wolf mouth), thymus gland, pathology of parathyroid glands . Because the isotretinoin has a high lipophilicity, it is very likely that it enters the breast milk. Due to possible side effects, Roaccutane® should not be given to nursing mothers.

Dosing and Administration:

Standard dosing regimen

Inside, with meals once or twice a day.

The therapeutic effectiveness of the drug Roaccutane® and its side effects depend on the dose and vary in different patients. This dictates the need for an individual dose selection during treatment.

Treatment with Roaccutane® should be started at a dose of 0.5 mg / kg per day. In most patients, the dose varies from 0.5 to 1.0 mg / kg of body weight per day. Patients with very severe forms of disease or with acne of the trunk may need higher daily doses - up to 2.0 mg / kg. It has been proved that the frequency of remission and the prevention of relapses are optimal when using a course dose of 120-150 mg / kg (per treatment course), so the duration of therapy in specific patients varies depending on the daily dose. Complete remission of acne is often achieved in 16-24 weeks of treatment. In patients who are very poorly tolerated the recommended dose, treatment can continue at a lower dose, but spend it longer.

In most patients, acne completely disappears after a single course of treatment. With a clear relapse, a second course of treatment with Roaccutane® is shown at the same daily and exchange rate as the first.Since the improvement can continue up to 8 weeks after drug withdrawal, the repeated course should be appointed no earlier than the end of this period.

Dosing in special cases

In patients with severe renal failure, treatment should begin with a lower dose (eg, 10 mg / day) and then increase to 1 mg / kg / day or the maximum tolerated (but not more than a maximum daily dose of 1 mg / kg). The daily dose should be rounded down to the nearest smaller number of whole capsules.

Side effects:

Most side effects of the drug Roaccutane® depend on the dose. As a rule, with the appointment of recommended doses, the ratio of benefit and risk, taking into account the severity of the disease, is acceptable for the patient. Usually, side effects are reversible after dose adjustment or drug withdrawal, but some may persist after discontinuation of treatment.

Symptoms associated with hypervitaminosis A: dry skin, mucous membranes, incl. lips (cheilitis), nasal cavity (bleeding), laryngopharynx (hoarseness), eye (conjunctivitis, reversible corneal opacity and intolerance of contact lenses).

Skin and its appendages: rash, itching, face erythema / dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased granulation tissue proliferation, persistent thinning of hair, reversible hair loss, fulminant forms of acne, hirsutism, hyperpigmentation, photosensitivity, photo allergy, slight trauma of the skin, peeling of the palms skin and soles. At the beginning of treatment, there may be an exacerbation of acne, which lasts for several weeks.

Musculoskeletal system: pain in the muscles with increased activity of creatine phosphokinase (CKK) in the serum or without it, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, reduction of bone density, premature closure of epiphyseal growth zones, other bone changes, tendinitis.

Central nervous system and psychic sphere: behavioral disorders, depression, suicide attempts, suicide, psychosis, excessive fatigue, headache, increased intracranial pressure ("pseudotumor brain": headache, nausea, vomiting, visual impairment, optic nerve edema), convulsions.

Sense organs: violation of visual acuity, photophobia,disturbance of dark adaptation (decrease in sharpness of twilight vision), violation of color perception (passing after drug discontinuation), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, xerophthalmia, hearing impairment at certain sound frequencies.

Gastrointestinal tract: nausea, diarrhea, inflammatory bowel disease (colitis, ileitis), bleeding, dryness of the oral mucosa, bleeding from the gums, inflammation of the gums; pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg / dL), including with fatal outcome. Transient and reversible increase in hepatic transaminase activity, hepatitis. In many of these cases, the changes did not go beyond the limits of the norm and returned to the baseline during treatment, but in some situations it was necessary to reduce the dose or cancel Roaccutane®.

Respiratory system: bronchospasm (more often in patients with bronchial asthma in anamnesis). Blood System: anemia, a decrease in hematocrit, leukopenia, neutropenia, an increase or decrease in the number of platelets, an increase in the rate of erythrocyte sedimentation (ESR).

Laboratory indicators: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, a decrease in the concentration of high-density lipoproteins, hyperglycemia. During the administration of Roaccutane®, cases of newly diagnosed diabetes mellitus. In some patients, especially those engaged in intensive physical activity, individual cases of increased activity of CK in the serum are described.

The immune system: Local or systemic infections caused by gram-positive pathogens (Staphylococcus aureus). Other: lymphadenopathy, hematuria, proteuria, vasculitis (Wegener's granulomatosis, allergic vasculitis), systemic hypersensitivity reactions, glomerulonephritis, back pain.

Postmarketing surveillance

During post-marketing surveillance, cases of severe skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis are described in the use of Roaccutane® (see also "Specific guidance").

When using the drug Roaccutane, especially in patients who performed intensive physical exertion, serious cases of rhabdomyolysis, often leading to hospitalization and in some cases fatal outcome, were reported.

Overdose:In case of an overdose, signs of hypervitaminosis A may appear. In the first few hours after an overdose, gastric lavage may be necessary.

Interaction:Because of the possible increase in symptoms of hypervitaminosis A, simultaneous administration of Roaccutane® and vitamin A (retinol) and other oral retinoids should be avoided.

Since tetracyclines can also cause an increase in intracranial pressure, their use in combination with Roaccutane® is contraindicated.

Isotretinoin may impair the effectiveness of progesterone preparations, so do not use contraceptives containing small doses of progesterone. Combined use with local keratolytic or exfoliative drugs for the treatment of acne is contraindicated because of the possible increase in local irritation.

Special instructions:

Roaccutane® should be prescribed only by physicians, preferably dermatologists with experience in using systemic retinoids and who are aware of the risk of teratogenicity of the drug. Patients, both female and male, must provide a copy of the brochure with information for the patient.

To avoid accidental drug exposure to other people, patients who receive or shortly before (1 month) receive Roaccutane®, donors can not be taken.

It is recommended to monitor liver function and hepatic enzymes before treatment, 1 month after its onset, and then every 3 months or according to indications. There was a transient and reversible increase in hepatic transaminases, in most cases within the limits of normal values. If the activity of hepatic transaminases exceeds the norm, it is necessary to reduce the dose of the drug or to cancel it.

The concentration of serum lipids in the serum should be determined before the treatment, 1 month after the start, and then every 3 months or according to the indications. Usually lipid concentrations are normalized after dose reduction or drug withdrawal, as well as dieting. It is necessary to monitor a clinically significant increase in triglyceride concentration, since their elevation above 800 mg / dL or 9 mmol / l may be accompanied by the development of acute pancreatitis, possibly fatal. With persistent hypertriglyceridemia or symptoms of pancreatitis, Roaccutane® should be discontinued.In rare cases, patients treated with Roaccutane® are characterized by depression, psychotic symptoms and very rarely suicidal attempts and suicide. Although their causal relationship with the use of the drug is not established, special care should be taken in patients with a history of depression and observe all patients for depression during treatment with the drug, if necessary referring them to the appropriate specialist. However, the discontinuation of Roaccutane® may not lead to the disappearance of symptoms and further monitoring and treatment may be required.

In rare cases, at the beginning of therapy, there is an exacerbation of acne, which occurs within 7-10 days without correction of the dose of the drug.

A few years after the use of Roaccutane® for the treatment of dyskeratoses with a total exchange rate and duration of therapy higher than those 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, you should first carefully evaluate the ratio of possible benefits and risks.

Patients receiving Roaccutane® are advised to use a moisturizing ointment or body cream, lip balm to reduce dryness of the skin and mucous membranes at the beginning of therapy. In post-marketing surveillance, the use of Roaccutane® has described cases of severe skin reactions such as erythema multiforme, syndrome

Stevens-Johnson, toxic epidermal necrolysis. These phenomena can be serious and lead to loss of ability to work, life-threatening conditions, hospitalization or fatal outcome. Patients receiving Roaccutane® need careful monitoring to detect severe skin reactions and, if necessary, to decide whether to discontinue the drug.

Against the background of taking Roaccutane ®, pains in muscles and joints, an increase in serum CKK activity, which can be accompanied by a decrease in the tolerance of intensive physical activity are possible.

It should avoid deep chemical dermabrasion and laser treatment in patients receiving Roaccutane®, and also within 5-6 months after the end of treatment because of the possibility of increased scarring in atypical sites and (rarely) the occurrence of hyper- and hypopigmentation.During treatment with Roaccutane® and within 6 months after it, hair removal with wax applications can not be performed because of the risk of detachment of the epidermis, development of scarring and dermatitis.

Since some patients may experience a reduction in the severity of twilight vision, which sometimes persists after the end of therapy, patients should be informed about the possibility of this condition, recommending them to use caution when driving a car at night. The state of visual acuity needs to be carefully monitored. Dryness of the conjunctiva of the eyes, corneal opacity, deterioration of twilight vision and keratitis usually occur after the drug is withdrawn. With dry eye mucosa, you can use moisturizing ointment applications or artificial tears. It is necessary to observe patients with dryness of the conjunctiva for possible development of keratitis. Patients presenting complaints of vision should be referred to an ophthalmologist and consider whether it is advisable to cancel the drug Roaccutane®. If intolerance of contact lenses for the duration of therapy should be used glasses.

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

Rare cases of development of benign intracranial hypertension ("pseudocarcinoma of the brain") are described, including. when combined with tetracyclines. In such patients, Roaccutane® should be immediately discontinued.

When therapy with Roaccutane ®, inflammatory bowel disease may occur. In patients with severe hemorrhagic diarrhea, Roaccutane® should be immediately discontinued.

Rare cases of anaphylactic reactions, which occurred only after the previous external application of retinoids, are described. Severe allergic reactions dictate the need to discontinue the drug and carefully monitor the patient. Patients in the high-risk group (with diabetes, obesity, chronic alcoholism, or fat metabolism disorders) may need more frequent laboratory monitoring of glucose and lipid concentrations with Roaccutane®. There is a more frequent definition of glycemia in the presence or suspected of diabetes.

The presence of drugs in the environment should be minimized. Do not dispose of Roaccutane® with sewage or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

Effect on the ability to drive transp. cf. and fur:During the period of treatment, extreme care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions. Since some patients may experience a decrease in the sharpness of the twilight vision, which sometimes persists after the end of therapy, patients should be informed about the possibility of this condition, recommending them to use caution when driving a car and working with cars and mechanisms at night.

Form release / dosage:

Capsules 10 mg and 20 mg.

Packaging:10 capsules per blister PVC / PE / PVDC / A1 or PVC / PVDC / A1 or PVC / A1. 3 or 10 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:Store at a temperature of no higher than 25 ° C in a place protected from light and moisture.Keep out of the reach of children.

Shelf life:3 years. The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013958 / 01

Date of registration:01.10.2007

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp21.09.2015

Illustrated instructions

Instructions

Roaccutane® (Roaccutane®)