Sotret, 10 mg capsules 30 pcs

Pharmaceutical group:

Tissue regeneration stimulator.

Pharmic action:

Retinoid for systemic therapy of acne

Isotretinoin is the stereoisomer of fully trans-retinoic acid (tretinoin). The exact mechanism of action of Sotret is not yet clear, but it has been established that improvement in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and histologically confirmed reduction in their size. In addition, the anti-inflammatory effect of isotretinoin on the skin has been proven.

Sotret suppresses the proliferation of sebocytes and acts on acne by restoring the normal process of cell differentiation. Sebum is the main substrate for growth of Propionibacterium acnes, so reducing sebum production suppresses bacterial duct colonization.

Pharmacokinetics:

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

Intake.

The absorption of isotretinoin from the gastrointestinal tract varies. The absolute bioavailability of isotretinoin has not been determined because there is no human formulation for intravenous use. However, extrapolation of data obtained in an experiment in dogs suggests 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.

Eating isotretinoin with food increases bioavailability by a factor of 2 compared to fasting.

Distribution.

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

The distribution volume of isotretinoin in humans was not determined because there is no dosage form for intravenous administration.
Equilibrium blood concentrations of isotretinoin (C min ss) in patients with severe acne who received 40 mg of the drug twice daily ranged from 120 to 200 ng/ml. The 4-oxo-isotretinoin concentrations in these patients were 2.5 times higher than those of isotretinoin. There is insufficient data on isotretinoin tissue penetration in humans. Concentrations of isotretinoin in the epidermis are half as high as in serum.

Metabolism.

There are three main metabolites detected in plasma after ingestion: 4-oxo-isotretinoin, tretinoin (fully trans-retinoic 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 also glucuronides, but the structure of not all metabolites has been established.

The metabolites of isotretinoin have biological activity 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.

Because in vivo isotretinoin and tretinoin (fully trans-retinoic 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 metabolized by isomerization. In the pharmacokinetics of isotretinoin in humans the entero-hepatic circulation may play a significant role.

In vitro metabolism studies have shown that several CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. None of the isoforms seems to play a dominant role. Sotret and its metabolites have no significant effect on the activity of CYP enzymes.

Elimination.

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

Isotretinoin refers to natural (physiological) retinoids. Endogenous retinoid concentrations recover about 2 weeks after the end of Sotret.

Pharmacokinetics in special clinical cases.

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

Indications

Severe acne (cystic nodules, conglobate acne or acne with risk of scarring).

Acne that is not amenable to other therapies.

Active ingredient

Composition

Active ingredient: isotretinoin 10 mg.

Excipients: hydrogenated soybean oil – 7.65 mg, hydrogenated vegetable oil – 32.13 mg, white beeswax – 9.18 mg, edetate disodium – 0.08 mg, butylhydroxyanisole – 0.016 mg, refined soybean oil – 100.944 mg.

Jelatin capsule: gelatin -56.00 mg, glycerol – 29.277 mg, iron oxide red dye – 0.0325 mg, titanium dioxide – 0.190 mg, purified water – q.s, Liquid paraffin light* – q.s., isopropanol* – q.s.
Food black ink S-1-17823 – 0.75 mg.

The composition of food black ink S-1-17823: shellac 45% (20% esterified) in ethanol – 0.333 mg, iron oxide black dye – 0.175 mg, isopropanol* – 0.202 mg, n-butanol* – 0.017 mg, propylene glycol – 0.015 mg, ammonium hydroxide* – 0.008 mg.

How to take, the dosage

Standard dosing regimen
Orally, with meals once or twice daily.

Therapeutic efficacy of Sotret and its side effects are dose-dependent and vary from patient to patient. This dictates the need for individualized dose selection during treatment.

Treatment with Sotret 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.

The rate of remission and relapse prevention have been shown to be optimal with 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 is often achieved in 16-24 weeks of treatment. In patients who are very poorly tolerant of the recommended dose, treatment can be continued at a lower dose, but for longer periods of time.

In most patients, acne completely disappears after a single course of treatment. If there is a clear recurrence, a second course of treatment with Sotret at the same daily and course dose as the first is indicated. Because improvement may continue up to 8 weeks after withdrawal, a second course should not be prescribed until after this time.

Dosing in special cases

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

Interaction

Because of the possible worsening of symptoms of hypervitaminosis A, concomitant administration of Sotret and vitamin A should be avoided.

Because tetracyclines may also cause increased intracranial pressure, their use in combination with Sotret is contraindicated.

Isotretinoin may weaken the effectiveness of progesterone preparations, so low-dose progesterone contraceptives should not be used Combined use with topical keratolytic or exfoliative medications for the treatment of acne is contraindicated because of the potential for increased local irritation.

Special Instructions

Sotret should only be prescribed by physicians, preferably dermatologists, who are experienced in the use of systemic retinoids and are aware of the risk of teratogenicity of the drug. To avoid accidental exposure of other people to the drug, donor blood should not be taken from patients who are receiving or have received Sotret or have received Sotret shortly before (1 month).

It is recommended to monitor liver function and liver enzymes before treatment, 1 month after it starts, and then every 3 months or as indicated. Transient and reversible increase in liver transaminases has been noted, in most cases within normal values. If the level of liver transaminases exceeds normal values, the drug dose should be reduced or the drug should be discontinued.

The 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. Usually lipid concentrations normalize after dose reduction or discontinuation of the drug, as well as with diet. It is necessary to control clinically significant increase in triglycerides, since their rise above 800 mg/dL or 9 mmol/L may be accompanied by the development of acute pancreatitis, possibly with fatal outcome.

In case of persistent hypertriglyceridemia or symptoms of pancreatitis, Sotret should be discontinued. In rare cases, depression, psychotic symptoms and very rarely suicidal attempts have been described in patients receiving Sotret.

While a causal relationship with use has not been established, particular care should be taken in patients with a history of depression and all patients should be monitored for depression during treatment with the drug, with referral to an appropriate specialist if necessary. However, withdrawal of Sotret may not result in disappearance of symptoms and further monitoring and treatment by a specialist may be necessary. In rare cases, an acne flare-up is noted at the start of therapy, which resolves within 7-10 days without adjusting the dose of the drug.

A few years after the use of Sotret for the treatment of dyskeratoses at a total course dose and duration of therapy higher than recommended for acne therapy, bone changes developed, including premature closure of epiphyseal growth zones, hyperostosis, and calcification of ligaments and tendons. Therefore, when prescribing the drug to any patient, the ratio of possible benefits to risks should be carefully evaluated beforehand.

Patients receiving Sotret are recommended to use moisturizing ointment or body cream, lip balm to reduce dryness of skin and mucous membranes at the beginning of therapy. Against the background of taking Sotret, muscle and joint pain, increased serum creatinine phosphokinase may occur, which may be accompanied by decreased tolerance of intense physical activity.

Deep chemical dermoabrasion and laser treatment should be avoided in patients receiving Sotret and for 5-6 months after completion of treatment because of the possibility of increased scarring in atypical sites and the occurrence of hyper- and hypopigmentation. During Sotret treatment and for 6 months after treatment, waxing should not be performed because of the risk of detachment of the epidermis, scarring, and dermatitis.

Because some patients may have decreased visual acuity at night, which sometimes persists after therapy ends, patients should be informed about the possibility of this condition, advising them to exercise caution when driving at night. Visual acuity should be monitored closely.

Dryness of the conjunctiva, corneal opacities, worsening of night vision, and keratitis usually go away after discontinuation of the drug. If the mucosa is dry, moisturizing eye ointments or artificial tears may be used.

Patients with dry conjunctivae should be monitored for possible keratitis. Patients with visual complaints should be referred to an ophthalmologist and consideration should be given as to whether Sotret should be withdrawn.

If contact lenses are intolerant, glasses should be used for the duration of therapy. Exposure to sunlight and UV rays should be limited. Sunscreens with a high SPF of at least 15 should be used if necessary.

Rare cases of benign intracranial hypertension (“pseudo brain tumor”) have been described, including when combined with tetracyclines. Sotret should be stopped immediately in such patients. Inflammatory bowel disease may occur during therapy with Sotret. In patients with severe hemorrhagic diarrhea it is necessary to cancel Sotret immediately.

Rare cases of anaphylactic reactions have been described that occurred only after prior external application of retinoids. Severe allergic reactions dictate that the drug must be withdrawn and the patient must be closely monitored.

High-risk patients (with diabetes mellitus, obesity, chronic alcoholism or fat metabolism disorders) may require more frequent laboratory monitoring of glucose and lipid levels during treatment with Sotret. If diabetes is present or suspected, more frequent glycemic determination is recommended.

Contraindications

– Pregnancy, lactation
– hepatic insufficiency, hypervitaminosis A, marked hyperlipidemia, concomitant therapy with tetracyclines.
– Hypersensitivity to the drug or its components.
– Childhood under 12 years.

With caution:

Depression in the history, diabetes mellitus, obesity, disorders of lipid metabolism, alcoholism.

Side effects

Most of the side effects of Sotret are dose-dependent. Generally, the recommended doses have a benefit to risk ratio that is acceptable to the patient, given the severity of the disease. Usually side effects are reversible after adjusting the dose or withdrawing the drug, but some may persist after stopping treatment.

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

The skin and its appendages; rash, itching, facial erythema/dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased granulation tissue growth, persistent thinning of hair, reversible hair loss, fulminant acne, hirsutism, hyperpigmentation, photo sensitization, photoallergy, mild skin trauma. At the beginning of treatment, acne flare-ups may occur, persisting for several weeks.

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

Central nervous system and mental sphere: behavioral disorders, depression, headache, increased intracranial pressure (“pseudo brain tumor”: headache, nausea, vomiting, visual disturbances, optic nerve edema), seizures.

Sensory organs: individual cases of visual acuity disorders, photophobia, dark adaptation disorders (decreased acuity of crepuscular vision), rarely – color vision 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, diarrhea, inflammatory bowel disease (colitis, ileitis), bleeding; pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg/dL). Rare cases of pancreatitis with fatal outcome have been described. Transient and reversible increase in liver transaminases activity, 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 Sotret.

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

Blood system: anemia, decreased hematocrit, leukopenia, neutropenia, increased or decreased number of platelets, accelerated sedimentation.

Laboratory parameters: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, decreased high-density lipoproteins, rarely -hyperglycemia. During administration of Sotret, cases of newly diagnosed diabetes mellitus have been reported. In some patients, especially those engaged in intensive physical activity, some cases of increased serum CPK 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.

Overdose

In an overdose, there may be signs of hypervitaminosis A.

In the first few hours after an overdose, gastric lavage may be necessary.

Pregnancy use

Pregnancy is an absolute contraindication for therapy with Sotret. If pregnancy occurs, despite the warnings, during treatment or within a month after completion of therapy, there is a very high risk of the birth of a child with severe malformations.

Isotretinoin is a drug with strong teratogenic effects. If a pregnancy occurs while a woman is taking isotretinoin orally (in any dose or for any length of time) there is a very high risk that the baby will be born with malformations.
Sotret is contraindicated in women of childbearing age unless the woman meets all of the following criteria:

– she must suffer from a severe form of acne that is resistant to conventional treatments;
– she must surely understand and follow the doctor’s instructions;
– she must be informed by her doctor of the risk of pregnancy during Sotret treatment, within one month thereafter, and urgent consultation if pregnancy is suspected;
– she must be warned about possible contraceptive failure;
– she must confirm that she understands the precautions;
– she must understand the need for and continually use effective contraception for one month before, during and one month after treatment with Sotretem (see She must be able to obtain a negative, reliable pregnancy test within 11 days prior to starting Sotret drug therapy; a pregnancy test is highly recommended monthly during treatment and 5 weeks after treatment ends;
-she should not start Sotret drug therapy until day 2-3 of her next normal menstrual cycle;
-she should understand the need for effective contraception.

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

The physician must be sure that:
– the patient has severe acne (cystic nodules, conglobate acne, or acne at risk for scarring); acne not amenable to other therapies;
– a negative reliable pregnancy test was obtained before starting the drug, during therapy, and 5 weeks after therapy; dates and results of the pregnancy test should be documented;
– the patient is using at least one, preferably two, effective methods of contraception, including a barrier method, within one month before starting Sotret treatment, during treatment, and within one month after treatment ends;
– the patient is able to understand and comply with all of the above requirements for pregnancy prevention;
– the patient meets all of the above conditions.

Pregnancy test

It is current practice to perform the pregnancy test with a minimum sensitivity of 25 dU/mL on the first 3 days of the menstrual cycle:

Pre-therapy:
– To rule out possible pregnancy before starting contraception, the result and date of the initial pregnancy test must be recorded by a physician. In patients with irregular periods, the timing of the pregnancy test depends on sexual activity and should be performed 3 weeks after unprotected intercourse. The doctor should inform the patient about the contraceptive methods.
– The pregnancy test is performed on the day of the Sotret prescription or 3 days before the patient’s visit to the doctor. The specialist should record the test results. The drug can be prescribed only to patients receiving effective contraception for at least 1 month before starting therapy with Sotret.

During therapy:
The patient should see her doctor every 28 days. The need for monthly pregnancy testing is determined according to local practice and taking into account sexual activity, previous menstrual irregularities. If indicated, the 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.

The end of therapy:
Five weeks after the end of therapy, a test is performed to rule out pregnancy.

The prescription for Sotret to a woman capable of childbearing can be prescribed only for 30 days of treatment, continuation of therapy requires a new prescription of the drug by the doctor. It is recommended that the pregnancy test, prescription and dispensing be done on the same day.
Dispense Sotret in a pharmacy only within 7 days of issuing the prescription.

Complete information about teratogenic risks and strict adherence to measures to prevent pregnancy should be given to both men and women.

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