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

Active substance
Isotretinoin	10 mg	20 mg
Excipients	sufficient amount until the contents of the capsule are obtained by mass 164 mg 328 mg
[Soybean oil refined beeswax	133.44 mg	266.88 mg
Beeswax	0.82 mg	1.64 mg
Soybean bean oil hydrogenated	19.68 mg	39.36 mg
Butylhydroxyanisole	0.04 mg	0.08 mg
Disodium edetate (Trilogy B)]	0.02 mg	0.04 mg
Excipients	sufficient amount until shell capsules with a mass 116 mg 192 mg
[Gelatin medical	84.368 mg	139.748 mg
Glycerol (glycerol)	30.52 mg	50.45 mg
Methylparahydroxybenzoate (Methylparaben)	0.59 mg	0.98 mg
Propyl parahydroxybenzoate (propylparaben)	0.084 mg	0.14 mg
Titanium dioxide	0.38 mg	0.634 mg
Iron Oxide Red Dye Oxide	0.058 mg	0.048 mg
Capsule weight:	280 mg	520 mg

Description:

Dosage 10 mg - soft gelatin capsules of brownish-red color, oblong with a longitudinal seam.

Dosage 20 mg - capsules are soft gelatinous two-color: one half is brownish-red, the other half is white with a yellowish hue of color, oblong with a longitudinal seam.

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

Pharmacotherapeutic group:Treatment for acne

ATX: & nbsp

D.10.B.A.01 Isotretinoin

Pharmacodynamics:

Retinoid for systemic therapy of acne.

Isotretinoin is a stereoisomer of fully trans-retieic acid (tretinoin). The precise mechanism of action of isotretinoin has not yet been clarified, but it has been established that the improvement of the clinical picture of severe acne forms 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.

Promotes the normalization of terminal differentiation of keratinocytes, inhibits the hyperproliferation of the epithelium of the excretory ducts of the sebaceous glands, the formation of detritus and facilitates its evacuation. Due to this, the production of sebum decreases, its isolation is facilitated, the composition is normalized, the inflammatory reaction around the glands is reduced.With systemic application it has antiseboric, sebostatic, anti-inflammatory, kerato-and immunomodulatory effects; strengthens the regeneration processes in the skin.

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 the "hepatic" enzymes involved in the metabolism of drugs.

Suction

Suction from the gastrointestinal tract fluctuates. Absolute bioavailability was not determined, since there is no form of release for intravenous use in humans. According to preclinical studies, it can be assumed that bioavailability is low and variable. The intake of isotretinoin with food increases bioavailability by 2 times compared with fasting. After oral administration at a dose of 80 mg, the time to reach the maximum concentration (TCmah) isotretinoin - 2-4 hours maximum concentration (Cmax) 310 ng / ml (188-473 ig / ml). The concentration in the plasma is 1.7 times higher than in the blood, due to the poor penetration of isotretinoin into erythrocytes.

Distribution

Communication with plasma proteins (mainly with albumin) is 99.9%, therefore 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 amount. The volume of isotretinoin distribution in humans has not been determined, since there is no dosage form for intravenous administration.

After oral administration at a dose of 40 mg 2 times a day, the equilibrium concentration (Css) isotretinoin - 120-200 ng / ml, 4-oxo-isotretinoin (the main metabolite) is 2.5 times greater than that of isotretinoin. The concentration of isotretinoin in the epidermis is 2 times lower than in serum. Data on the penetration of isotretinoin in human tissue is not enough. Metabolism

Metabolized with the formation of 3 major biologically active metabolites: 4-oxo-isotretinoin (chief), tretinoin (all-trans retinoic acid) and 4-oxo-retinoin, and less significant metabolites, including glucuronides, but not all metabolites.

The main metabolite is 4-oxo-isotretinoin, plasma concentrations of which in the equilibrium state are 2.5 times higher than the concentrations of the initial preparation. Because the in vivo isotretinoin and tretinoin reversibly transform 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. The greatest value in the metabolism of isotretinoin isoenzymes of the system CYP.

Excretion

After ingestion of radioactively labeled isotretinoin in urine and feces approximately the same amount of isotretinoin is found. Half-life terminal phase for an unchanged drug in patients with acne is, on average, 19 hours. The half-life of the terminal phase for 4-oxo-isotretinoin,apparently, more and equals, on average, 29 hours. Isotretinoin refers to natural (physiological) retinoids. Endogenous concentrations of rastinoids are restored approximately 2 weeks after the end of the drug.

Pharmacokinetics in special clinical cases

Because the isotretinoin Contraindicated in the violation of liver function, data on the pharmacokinetics of the drug in this group of patients are limited.Renal failure does not affect the pharmacokinetics of isotretinoin.

Indications:Heavy forms of acne (nodular-cystic, conglobate acne or acne with the risk of scarring) and not amenable to other types of therapy.

Contraindications:

- liver failure;

- hypervitaminosis A;

- concomitant therapy with tetracyclines;

- children's age till 12 years;

- severe hyperlipidemia;

- Pregnancy is established and planned;

- the period of breastfeeding;

- hypersensitivity to isotretinoin and any other component of the drug.

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

Pregnancy and lactation:

Pregnancy is an absolute contraindication for isotretinoin therapy. Isotretinoin - 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.

Isotretinoin is contraindicated in women of childbearing age, unless the condition of a woman satisfies all of the following criteria:

- Severe form of acne, resistant to conventional methods of treatment.

- The patient should understand and follow the doctor's instructions.

- The patient should be informed by the doctor about the dangers of pregnancy during treatment with isotretinoim, within one month after it and urgent consultation in case of suspected pregnancy.

- The patient should be warned about the possible ineffectiveness of contraceptives.

- The patient must confirm that she understands the nature of the precautionary measures.

- The patient should understand the need and continuously use effective methods of contraception within one month prior to treatment with isotretinoin, during treatment and for a month after its termination; It is desirable to use at the same time 2 different methods of contraception, including the barrier method. Use of contraceptives during treatment with isotretinoin should be recommended even to women who do not usually use contraceptive methods due to infertility (except for patients who underwent a hysterectomy), amenorrhea, or who report that they do not have sex.

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 application of the drug Verocutan or 3 days before the patient's visit to the doctor. The specialist should register the test results. The drug can be used only by patients who receive effective contraception at least 1 month before the start of therapy with the drug Verocutan.

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 the drug Verokutan to a woman capable of childbirth 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 the drug Verocutan in the pharmacy should be done only within 7 days from the date of prescription.

To male patients nola

Existing evidence suggests that in women exposure to a drug that comes from semen and semen from men who take isotretinoin, is not sufficient for the appearance of teratogenic effects of isotretinoin.

If, in spite of the precautionary measures taken, during the treatment with isotretinoin or within a month after its termination, the pregnancy does occur, there is a high risk of very serious fetal malformations (in particular, from the central nervous system, heart and large blood vessels). In addition, the risk of spontaneous miscarriages increases.

In the event of pregnancy, isotretinoin therapy is discontinued. You should discuss with your doctor whether to maintain your pregnancy. Heavy congenital malformations of the fetus in humans associated with the use of isotretinoin, including hydrocephalus, microcephaly, malformations of the cerebellum, anomalies of the external ear (microtia, narrowing or absence of the external auditory canal), microfaltalmia, cardiovascular anomalies (tetralogy of Fallot, transposition of the main vessels, defects of the septa), developmental defects of the face ("wolf mouth"), thymus gland, parathyroid gland pathology.

Lactation period

Because the isotretinoin has a high lipophilicity, it is very likely that it enters the breast milk. Because of possible side effects isotretinoin can not be used by nursing mothers.

Dosing and Administration:

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

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

The initial dose is 0.5 mg / kg / day.In most patients, the dose varies

from 0.5 to 1.0 mg / kg of body weight per day. In severe forms of the disease or patients

with a trunk acne may require a dose of up to 2 mg / kg / day.

The optimal course dose is 120 mg / kg - 150 mg / kg (per course), so the duration of therapy for a particular patient 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 Vera-kutan 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 severe chronic renal failure (XPS), the initial dose should be reduced to 10 mg / day, followed by an increase, no 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 isotretinoin depend on the dose. As a rule, with the appointment of recommended doses, the benefit-risk ratio, taking into account the severity of the disease, is acceptable to the patient. Usually, side effects are reversible after dose adjustment or drug withdrawal, but some may persist after discontinuation of treatment.

From the side of the system of skin and subcutaneous fat: rash, itching, face erythema / dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased granulation tissue growth, persistent thinning of hair, reversible hair loss, fulminant forms of acne, hirsutism, hyperpigmentation, photosensitivity, photo allergy, slight trauma to 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.

Symptoms associated with hypervitaminosis A:

dry skin, mucous membranes, including the lips (cheilitis), nasal cavity (bleeding), larynx, pharynx (hoarseness), eye (conjunctivitis, reversible corneal opacity, intolerance to contact lenses).

From the sense organs:

impairment of visual acuity, photophobia, reduction in visual acuity of the twilight vision, violation of color perception (passing after the drug discontinuation), lenticular cataract, keratitis, blepharitis, conjunctivitis, xerophthalmia. eye irritation, edema of the optic nerve (as a manifestation of intracranial hypertension); hearing impairment at certain audio frequencies.

FROMabout side of the musculoskeletal system:

pain in the muscles, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, other bone changes, tendinitis, decreased bone density, premature closure of epiphyseal growth zones.

From the central nervous system:

impaired behavior, depression, headache, increased intracranial pressure ("pseudotumor brain": headache, nausea, vomiting, impaired vision, edema of the optic nerve), seizures. Dizziness, drowsiness, sleep disturbance, lethargy, anxiety, nervousness, paresthesia, syncope, weakness, excessive fatigue.

FROMabout side of the mental sphere:

Suicidal thoughts, suicidal attempts, suicide, depression, aggression, emotional lability, psychosis.

From the reproductive side:

Menstrual irregularities

On the part of the respiratory system:

bronchospasm (more often in patients with bronchial asthma in anamnesis).

From the digestive system:

nausea, diarrhea, dryness of the oral mucosa, bleeding from the gums, inflammation of the gums, inflammatory bowel disease (colitis, ileitis), bleeding, esophagitis, ulcers of the esophagus. pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg / dL), including with fatal outcome. Transient and reversible increase in the activity of "liver" transaminases, hepatitis. In these cases, the changes did not go beyond the limits of the norm and returned to the initial indicators during the treatment, however in some situations it was necessary to reduce the dose or cancel isotretinoin.

From the laboratory indicators:

increased concentration of triglycerides (TG), cholesterol, uric acid, a decrease in the concentration of high-density lipoproteins (LIIBP) in blood plasma, hyperglycemia. In the course of taking isotretinoin, cases of newly diagnosed diabetes mellitus are described. In some patients, especially those engaged in intensive physical activity, cases of increased activity of creatine phosphokinase are described.

On the part of the blood system, the organs of hematopoiesis:

anemia, a decrease in the number of leukocytes, neutrophils, a decrease in hematocrit, an increase or decrease in the number of platelets, an acceleration of the rate of erythrocyte sedimentation (ESR).

From the immune system:

Local or systemic infections caused by gram-positive pathogens

(Staphylococcus aureus).

Other:

lymphadenopathy, hematuria, protsinuria, vasculitis (Wegener's granulomatosis, allergic vasculitis), systemic hypersensitivity reactions, glomeruloephritis, back pain.

Postmarketing surveillance

Overdose:

Symptoms:

In case of overdose, signs of hypervitaminosis A (dizziness, headache, drowsiness, nausea, vomiting, irritability) may appear.

Treatment: In the first few hours after an overdose, a gastric lavage may be necessary. In most cases, these phenomena are reversible, do not require treatment.

Interaction:

Simultaneous use with other retinoids (including acitretin, tretinoin, retinol, tazarotene, adapalen) increases the risk of hypervitaminosis A.

Tetracyclines (incl. minocycline) increase the risk of increased intracranial pressure, concurrent use with isotretinoin is contraindicated. Isotretinoin may impair the effectiveness of progesterone preparations, therefore, do not use contraceptives containing small doses of progesterone.

Combined use with local keratolytic drugs for the treatment of acne is not recommended because of the possible increase in local irritation.

Special instructions:

The drug Verocutan should be prescribed only by doctors, preferably dermatologists who have experience in the use of systemic retinoids and who are aware of the risk of teratogenicity of the drug.

Do not use with vulgar acne of mild and moderate degree of flow. During the treatment period and within 30 days after its termination, it is necessary to completely exclude blood sampling from potential donors to completely exclude the possibility of getting this blood to pregnant patients (high risk of teratogenic and embryotoxic action).

Women of reproductive age must use reliable contraceptive methods 4 weeks before, during, and within 1 month after the end of treatment. In the event of pregnancy, isotretinoin therapy is discontinued.You should discuss with your doctor whether to maintain your pregnancy.

There was a transient and reversible increase in the activity of "liver" transaminases, in most cases within the limits of normal values. It is recommended to monitor the activity of "liver" transaminases before treatment, 1 month after its onset, and then every 3 months or but readings. If the activity of "liver" transaminases exceeds the norm, it is necessary to reduce the dose of the drug or cancel it. It should also be determined the concentration of lyids in the serum on an empty stomach before the treatment, 1 month after the start, and then every 3 months or according to the indications. Usually, the concentrations of the lyids are normalized after the dose is reduced or the drug is discontinued, and also when the diet is observed. 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, the drug should be withdrawn.

In the presence of diabetes mellitus or suspected of it, a more frequent determination of the glucose concentration is recommended.

In rare cases, patients who received isotretinoin, described depression, psychotic symptoms and very rarely - suicidal attempts. Although their causal relationship with the use of the drug has not been established, special care should be taken in patients with a history of depression and observe all patients for depression during drug treatment, if necessary referring them to the appropriate specialist. However, the withdrawal of the drug may not lead to the disappearance of symptoms and further monitoring and treatment by a specialist may be required.

In rare cases, acute exacerbation of acne occurs at the beginning of isotretinoin therapy. which occurs within 7-10 days without dose adjustment.

A few years after the use of isotretinoin for the treatment of dyskeratosis at a common course 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, it is necessary to carefully estimate the relationship between possible benefit and risk.

Patients receiving isotretinoin, it is recommended to use moisturizing ointment or body cream, lip balm to reduce dryness of the skin and mucous membranes at the beginning of therapy.

During the post-marketing observation with the use of isotretinoin, cases of development of severe skin reactions such as multiform exudative erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis are described. These phenomena can be serious and lead to loss of ability to work, life-threatening conditions, hospitalization or fatal outcome. Patients receiving isotretinoin, need careful monitoring to identify severe skin reactions and, if necessary, to resolve the issue of drug withdrawal. Against the background of taking isotretinoin, pains in the muscles and joints, an increase in serum creatinine phosphokinase, which may be accompanied by a decrease in the tolerance of intensive physical activity.

Dermal chemical dermabrasion and laser treatment should be avoided in patients receiving isotretinoin, and also within 5-6 months after the end of treatment because of the possibility of increased scarring in atypical sites and the appearance of hyper- and hypopigmentation.During treatment with isotretinoin and within 6 months after it, hair removal with wax applications can not be carried out because of the risk of detachment of the epidermis, development of scarring and dermatitis.

Since some patients may experience a decrease in the sharpness of the twilight vision, which sometimes persists even after the end of therapy, patients should be informed about the possibility of this condition, recommending that they take care when driving 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 who complain about vision should be referred to an ophthalmologist and consider whether the drug should be withdrawn. If intolerance of contact lenses for the duration of therapy should be used glasses.

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

Rare cases of development of benign intracranial hypertension ("pseudocarcinoma of the brain") are described, including. when combined with tetracyclines. Such patients should immediately cancel the drug.

When therapy with the drug Verocutan may occur inflammatory bowel disease. In patients with severe hemorrhagic diarrhea, it is necessary to immediately stop taking the drug Verocutan.

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.

Effect on the ability to drive transp. cf. and fur:Due to the fact that in some patients there may be a decrease in the severity of twilight vision, during the treatment period it is necessary to be cautious when driving vehicles and engaging in other potentially dangerous activities at night.When taking the drug may cause such side effects as headache, dizziness, drowsiness, violation of visual acuity. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:Capsules 10 mg and 20 mg.

Packaging:

10 capsules in a contour mesh package from a three-layer polymer film consisting of a polyvinyl chloride / polyethylene / polyvinyl dichloride composition and an aluminum printed lacquer foil.

30 capsules in a polymer bottle, with polymer cover with control of the first opening with an insert of silica gel.

1 vial or 3, or 10 contour mesh packages together with instructions for use in a pack of cardboard.

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

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002988

Date of registration:07.05.2015 / 13.10.2015

Expiration Date:07.05.2020

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Information update date: & nbsp05.02.2017

Illustrated instructions

Instructions

Verocutan (Verokutan)