Roaccutane, capsules 10mg, 30pcs

Composition

One 10 mg capsule contains: Active ingredient:  isotretinoin — 10 mg; excipients: soy bean oil-107.92 mg, yellow beeswax-7.68 mg, hydrogenated soybean oil-7.68 mg, partially hydrogenated soybean oil-30.72 mg; capsule shell:  glycerol 85% – 31.275 mg, gelatin-75.64 mg, Karion 83 (hydrolyzed potato starch, mannitol, sorbitol) – 8.065 mg, iron oxide red dye (E 172) – 0.185 mg, titanium dioxide (E 171) — 1.185 mg;ink for writing on the capsule:  shellac, iron oxide black dye (E 172); it is allowed to use ready-made ink Opacode Black S-1-27794.

Pharmacological action

Pharmacotherapy group: Acne treatment agent

ATX code [D10BA01]

Pharmacological action

Retinoid for systemic treatment of acne

Isotretinoin is a stereoisomer of all-transretinoic acid (tretinoin). The exact mechanism of action of Roaccutane® has not yet been elucidated, but it has been established that the improvement in the clinical picture of severe forms of acne is associated with suppression of the activity of the sebaceous glands and histologically confirmed reduction in their size. In addition, the anti-inflammatory effect of isotretinoin on the skin has been proven.

Hyperkeratosis of the epithelial cells of the hair bulb and sebaceous gland leads to exfoliation of corneocytes in the duct of the gland and to blockage of the latter with keratin and excess sebaceous secretions. This is followed by the formation of comedones and, in some cases, the addition of 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, so reducing sebum formation suppresses bacterial colonization of the duct.

Pharmacokinetics

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

Suction

The absorption of isotretinoin from the gastrointestinal tract fluctuates. The absolute bioavailability of isotretinoin was not determined, since there is no form of release of the drug for intravenous use in humans. However, extrapolating the data obtained in the experiment on dogs suggests a rather low and variable systemic bioavailability.

In patients with acne, the maximum plasma concentrations (Cmax) at steady state after taking 80 mg of isotretinoin on an empty stomach were 310 ng / ml (range 188-473 ng / ml) and reached in 2-4 hours. Plasma isotretinoin concentrations are approximately 1.7 times higher than blood concentrations, due to poor penetration of isotretinoin into red blood cells.

Taking isotretinoin with food increases bioavailability by 2 times compared to taking it on an empty stomach.

Distribution

Isotretinoin binds strongly (99.9%) to plasma proteins, mainly 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 amount. The volume of distribution of isotretinoin in humans was not determined, since there is no dosage form for intravenous use.

Steady-state blood concentrations of isotretinoin (Smin ss) in patients with severe acne who took 40 mg of the drug 2 times a day ranged from 120 to 200 ng / ml. The concentrations of 4-oxo-isotretinoin in these patients were 2.5 times higher than those of isotretinoin. There is insufficient data on the penetration of isotretinoin into human tissues. The concentration of isotretinoin in the epidermis is two times lower than in the serum.

Metabolism

After oral use, three main metabolites are detected in plasma: 4-oxo-isotretinoin, tretinoin (completely transretinoic acid) and 4-oxo-retinoin. The main metabolite is 4-oxo-isotretinoin, whose plasma concentrations at steady state are 2.5 times higher than those of the initial drug. Less significant metabolites, including glucuronides, were also found, but the structure of not all metabolites was established.

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

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

Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans. In vitro metabolic studies have shown that several cytochrome P450 (CYP) enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. Apparently, none of the isoforms plays a dominant role in this process. Roaccutane® and its metabolites do not significantly affect the activity of CYP enzymes.

Deduction

After ingestion of radioactively labeled isotretinoin, approximately the same amount is detected in the urine and feces. The terminal half-life of an unchanged drug in patients with acne is an average of 19 hours. The terminal phase half-life of 4-oxo-isotretinoin appears to be longer, averaging 29 hours.

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

Pharmacokinetics in special clinical cases

Since isotretinoin is contraindicated in patients with impaired liver function, data on the pharmacokinetics of the drug in this group of patients are limited. Renal insufficiency does not affect the pharmacokinetics of isotretinoin.

Indications

Acne that does not respond to other types of therapy. Severe forms of acne (nodular-cystic, conglobate acne, or acne with a risk of scarring).

Use during pregnancy and lactation

Isotretinoin is a drug with a strong teratogenic effect. If pregnancy occurs during the period when a woman takes isotretinoin orally (in any dose and even for a short time), there is a very high risk of having a child with malformations. Roaccutane® is contraindicated in women of childbearing age, unless the woman’s condition meets all of the following criteria: : – she must have a severe form of acne that is resistant to conventional treatments;- she should accurately understand and follow the doctor’s instructions; – she should be informed by the doctor about the risk of pregnancy during treatment with Roaccutane® within one month after it and an urgent consultation if pregnancy is suspected: – she should be warned about the possible ineffectiveness of contraception;- she must confirm that she understands the nature of the precautions;- she should understand the need for and continuously use effective methods of contraception for one month before treatment with Roaccutane®, during treatment and for a month after it ends (see the section “Interaction with other drugs”); it is advisable to use 2 different methods of contraception at the same time, including barrier; – she should have a negative result of a reliable pregnancy test within 11 days before taking the drug; pregnancy test is strongly recommended to be performed monthly during treatment and 5 weeks after the end of therapy;- she should start treatment with Roaccutane® only on day 2-3 of the next normal menstrual cycle; – she should understand the need for mandatory visits to the doctor every month; – when treating for a relapse of the disease, she should constantly use the same effective methods of contraception for one month before starting treatment with Roaccutane®, during treatment and for a month after its completion, as well as undergo the same reliable pregnancy test;- she should fully understand the need for precautionary measures and confirm her understanding and desire to use reliable methods of contraception that the doctor explained to her. The use of contraceptives as indicated above during treatment with isotretinoin should be recommended even for women who do not normally use contraception due to infertility (with the exception of patients who have undergone a hysterectomy), amenorrhea, or who report that they are not sexually active.

The doctor should be sure that:

– the patient has a severe form of acne (nodular-cystic, conglobate acne or acne with a risk of scarring); acne that does not respond to other types of therapy;- a negative result of a reliable pregnancy test was obtained before taking the drug, during therapy, and 5 weeks after the end of therapy; the dates and results of the pregnancy test should be documented;- the patient uses at least 1, preferably 2 effective methods of contraception, including the barrier method, for one month before starting treatment with Roaccutane®, during treatment and for one month after it ends;- the patient is able to understand and fulfill all of the above requirements for pregnancy prevention;- the patient meets all of the above conditions.

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 therapy:

During therapy:

Roaccutane® should only be dispensed at the pharmacy within 7 days from the date of prescription. Full information about the teratogenic risk and strict adherence to measures to prevent pregnancy should be provided to both men and women. For male patients, nonexistent data indicate that in women, exposure to the drug coming from the semen and seminal fluid of men taking Roaccutane® is not sufficient to cause the teratogenic effects of Roaccutane®. Men should exclude the possibility of taking the drug by others, especially women. If, despite the precautions taken, pregnancy still occurs during treatment with Roaccutane® or within a month after its end, 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 discontinued. You should discuss the feasibility of preserving it with a doctor who specializes in teratology. Severe congenital malformations of the human fetus associated with the use of Roaccutane® have been documented, including hydrocephalus, microcephaly, cerebellar malformations, external ear abnormalities (microtia, narrowing or absence of the external auditory canal), microphthalmia, cardiovascular abnormalities (Fallot’s tetrad, transposition of the main vessels, septal defects), facial malformations (cleft palate), thymus gland, parathyroid gland pathology. Because isotretinoin is highly lipophilic, it is highly likely that it is released into breast milk. Due to possible side effects, Roaccutane® should not be prescribed to nursing mothers.

Contraindications

Pregnancy, breast-feeding, liver failure, hypervitaminosis A, severe hyperlipidemia, concomitant therapy with tetracyclines.

Hypersensitivity to the drug or its components.

Children under 12 years of age.

Side effects

Most of the side effects of Roaccutane are dose-dependent. As a rule, when prescribing the recommended doses, the benefit-risk ratio, taking into account the severity of the disease, is acceptable for the patient. Usually, side effects are reversible after dose adjustment or discontinuation of the drug, but some may persist after discontinuation of treatment.

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

Skin and its appendages: rash, pruritus, facial erythema / dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased growth of granulation tissue, persistent thinning of hair, reversible hair loss, fulminant forms of acne, hirsutism, hyperpigmentation, photosensitization, photoallergia, light skin injury. At the beginning of treatment, acne may worsen and persist for several weeks.

Musculoskeletal system: muscle pain with or without elevated serum CPK, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, other bone changes, tendonitis.

Central nervous system and mental sphere: behavioral disorders, depression, headache, increased intracranial pressure (“pseudotumor of the brain”: headache, nausea, vomiting, visual impairment, edema of the optic nerve), convulsive seizures.

Sensory organs: some cases of visual acuity disorders, photophobia, dark adaptation disorders (decreased twilight vision acuity), rarely-color perception disorders (passing after discontinuation of the drug), lenticular cataracts, keratitis, blepharitis, conjunctivitis, eye irritation, optic nerve edema (as a manifestation of intracranial hypertension); hearing impairment at certain sound frequencies.

Gastrointestinal tract: nausea, diarrhea, inflammatory bowel diseases (colitis, ileitis), bleeding; pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg / dl). Rare cases of pancreatitis with fatal outcome are described.

Transient and reversible increase in hepatic transaminase activity, isolated cases of hepatitis. In many of these cases, the changes did not go beyond the normal limits and returned to the initial values during treatment, but in some situations it was necessary to reduce the dose or cancel Roaccutane.

Respiratory organs: rarely-bronchospasm (more often in patients with a history of bronchial asthma).

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

Laboratory parameters: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, decreased high-density lipoprotein levels, rarely hyperglycemia. Cases of newly diagnosed diabetes mellitus have been reported while taking Roaccutane. In some patients, especially those engaged in intense physical activity, individual cases of increased serum creatinine kinase activity have been described.

The 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

Due to the possible increase in symptoms of hypervitaminosis A, simultaneous use of Roaccutane and vitamin A should be avoided.

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

Isotretinoin can weaken the effectiveness of progesterone medications, so you should not use contraceptives that contain small doses of progesterone.

Concomitant use with topical keratolytic or exfoliative preparations for the treatment of acne is contraindicated due to the possible increase in local irritation.

How to take, course of use and dosage

Standard dosage regimen

Inside, with a meal 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 the need for individual dose selection during treatment. Treatment with Roaccutane should begin with a dose of 0.5 mg / kg per day.

In most patients, the dose ranges from 0.5 to 1.0 mg / kg of 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 is proved that the frequency of remission and prevention of relapses 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 depending on the daily dose. Complete remission of acne can often be achieved in 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 it can be carried out longer.

In most patients, acne completely disappears after a single course of treatment. In case of an obvious relapse, a second course of treatment with Roaccutane is indicated in the same daily and course dose as the first one. Since the improvement can last up to 8 weeks after discontinuation of the drug, a second course should be prescribed no earlier than the end of this period.

Dosage in special cases

In patients with severe renal insufficiency, treatment should begin with a lower dose (for example,10 mg/day) and then increase to 1 mg/kg/day or the maximum tolerated dose.

Overdose

In case of overdose, signs of hypervitaminosis may appear.

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

Special instructions

Roaccutane should only be prescribed by physicians, preferably dermatologists, who have experience with systemic retinoids and are aware of the risk of teratogenicity of the drug.Both female and male patients should be provided with a copy of the patient information booklet. In order to avoid accidental exposure of the drug to the body of other people, patients who receive or shortly before (1 month) received Roaccutane should not take donor blood.

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

Fasting serum lipids should also be measured before treatment,1 month after initiation, and then every 3 months or as indicated. Usually, lipid concentrations normalize after dose reduction or discontinuation of the drug, as well as when following a diet. A clinically significant increase in triglyceride levels should be monitored, since their rise above 800 mg / dl or 9 mmol / L may be accompanied by the development of acute pancreatitis, possibly with a fatal outcome. If persistent hypertriglyceridemia or symptoms of pancreatitis occur, Roaccutane should be discontinued.

In rare cases, patients treated with Roaccutane have been described as having 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 all patients should be monitored for depression during treatment with the drug, if necessary referring them to the appropriate specialist. However, withdrawal of Roaccutane may not lead to the disappearance of symptoms and may require further monitoring and treatment by a specialist.

In rare cases, at the beginning of therapy, there is an exacerbation of acne, which passes within 7-10 days without dose adjustment. Several years after the use of Roaccutane for the treatment of dyskeratosis, bone changes, including premature closure of epiphyseal growth zones, hyperostosis, calcification of ligaments and tendons, developed at a total course dose and duration of therapy that was higher than recommended for acne treatment. Therefore, when prescribing the drug to any patient, the ratio of possible benefit and risk should be carefully evaluated beforehand.

Patients receiving Roaccutane are recommended to use a moisturizing ointment or body cream, lip balm to reduce dry skin and mucous membranes at the beginning of therapy.

Cases of severe skin reactions, such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported during post-marketing surveillance with the use of Roaccutane. These events can be serious and lead to disability, life-threatening conditions, hospitalization, or death. Patients receiving Roaccutane should be closely monitored to detect severe skin reactions and, if necessary, decide whether to discontinue the drug.

While taking Roaccutane, there may be pain in the muscles and joints, an increase in serum creatinine phosphokinase, which may be accompanied by a decrease in tolerance to intense physical activity.

Deep chemical dermoabrasion and laser treatment should be avoided in patients receiving Roaccutane, as well as for 5-6 months after the end of treatment, due to the possibility of increased scarring in atypical areas and the occurrence of hyper – and hypopigmentation. During treatment with Roaccutane and for 6 months after it, hair removal with wax applications should not be performed due to the risk of epidermal detachment, scarring and dermatitis.

Since some patients may experience a decrease in night vision acuity, which sometimes persists even after the end of therapy, patients should be informed about the possibility of this condition, advising them to exercise caution when driving at night. The state of visual acuity should be carefully monitored.

Dryness of the conjunctiva of the eyes, corneal opacities, deterioration of night vision and keratitis usually disappear after discontinuation of the drug. If the eye mucosa is dry, you can use applications of moisturizing eye ointment or artificial tear preparation. Patients with conjunctival dryness should be monitored for possible development of keratitis. Patients presenting with visual complaints should be referred to an ophthalmologist and consider discontinuing Roaccutane. If you are intolerant to contact lenses, glasses should be used during therapy.

You should limit your exposure to sunlight and UV rays. If necessary, use a sunscreen with a high protective factor value of at least 15 SPF.

Rare cases of benign intracranial hypertension (“pseudotumor of the brain”) are described, including when combined with tetracyclines. In such patients, Roaccutane should be discontinued immediately.

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

Rare cases of anaphylactic reactions that occurred only after previous external use of retinoids are described. Severe allergic reactions dictate the need to discontinue the drug and carefully monitor the patient.

High-risk patients (with diabetes mellitus, obesity, chronic alcoholism, or impaired fat metabolism) may require more frequent laboratory monitoring of glucose and lipid levels during treatment with Roaccutane. If diabetes is present or suspected, a more frequent blood glucose test is recommended.

Form of production

Capsules.

Storage conditions

Store at a temperature not exceeding 25°C, in a place protected from light and moisture. Keep out of reach of children.

Shelf

life is 3 years.

Active ingredient

Isotretinoin

Conditions of release from pharmacies

By prescription

Dosage form

Capsules

Indications

Severe Acne