Sotret, 20 mg capsules 30 pcs

Pharmgroup:

Tissue regeneration stimulator.

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

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 colonization of the ductus.

Pharmacokinetics:

Because the kinetics of isotretinoin and its metabolites are linear, 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.

Is absorption.
Absorption of isotretinoin from the gastrointestinal tract is variable. The absolute bioavailability of isotretinoin has not been determined because there is no human form of the drug 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 over a wide range of therapeutic concentrations 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 has not been determined because there is no dosage form for intravenous administration.

The equilibrium blood concentrations (C min ss) of isotretinoin 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 the tissue penetration of isotretinoin in humans. Concentrations of isotretinoin in the epidermis are half as high as in serum.

Metabolism.
After oral administration, three major metabolites are detected in plasma: 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 liver dysfunction, 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 forms of acne (nodulocystic, conglobate acne or acne with risk of scarring).

Acne that does not respond to other types of therapy.

Pharmacological effect

Pharmaceutical group:

tissue regeneration stimulator.

Pharmaceutical action:

Retinoid for systemic treatment of acne

Isotretinoin is a stereoisomer of all-trans retinoic acid (tretinoin). The exact mechanism of action of Sotret has not yet been clarified, 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 a histologically confirmed reduction in their size. In addition, isotretinoin has been shown to have anti-inflammatory effects on the skin.

Hyperkeratosis of epithelial cells of the hair follicle and sebaceous gland leads to desquamation of corneocytes into the gland duct and to blockage of the latter with keratin and excess sebaceous secretion. This is followed by the formation of a comedone and, in some cases, the addition of an inflammatory process.

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

Pharmacokinetics:

Since the kinetics of isotretinoin and its metabolites is 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 the metabolism of drugs.

Suction.
Absorption of isotretinoin from the gastrointestinal tract varies. The absolute bioavailability of isotretinoin was not determined, since there is no release form of the drug for intravenous use in humans.

However, extrapolation of data obtained in an experiment in dogs suggests a rather low and variable systemic bioavailability. In patients with acne, 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 were achieved after 2-4 hours. Plasma concentrations of isotretinoin 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 is highly (99.9%) bound to plasma proteins, mainly albumin, so that over a wide range of therapeutic concentrations, 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 has not been determined because there is no dosage form available for intravenous administration.

Equilibrium concentrations of isotretinoin in the blood (C min 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 tissues in humans. Concentrations of isotretinoin in the epidermis are two times lower than in serum.

Metabolism.
After oral administration, three main metabolites are found in plasma: 4-oxo-isotretinoin, tretinoin (all-trans retinoic acid) and 4-oxo-retinoin.

The main metabolite is 4-oxo-isotretinoin, whose plasma concentrations at steady state are 2.5 times higher than the concentrations of the parent drug. Less significant metabolites have also been discovered, including glucuronides, but the structure of not all metabolites has been established.

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

Because isotretinoin and tretinoin (all-trans retinoic acid) are reversibly converted into each other in vivo, the metabolism of tretinoin is related to the metabolism of isotretinoin. 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 metabolism studies have shown that several 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 case. Sotret and its metabolites do not have a significant effect on the activity of enzymes of the CYP system.

Excretion.

After oral administration of radiolabeled isotretinoin, approximately equal amounts are found in urine and feces. The terminal phase half-life for unchanged drug in patients with acne averages 19 hours. The terminal phase half-life for 4-oxo-isotretinoin appears to be longer, averaging 29 hours.

Isotretinoin is a natural (physiological) retinoid. Endogenous concentrations of retinoids are restored approximately 2 weeks after the end of Sotret’s administration.

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 failure does not affect the pharmacokinetics of isotretinoin.

Special instructions

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

To avoid accidental effects of the drug on the body of other people, donated blood should not be taken from patients who are receiving or who have recently (1 month) received Sotret.

It is recommended to monitor liver function and liver enzymes before treatment, 1 month after treatment, and then every 3 months or as indicated. A transient and reversible increase in liver transaminases was noted, in most cases within normal values. If the level of liver transaminases exceeds the norm, it is necessary to reduce the dose of the drug or discontinue it. Fasting serum lipid levels should also be determined before treatment, 1 month after initiation, and then every 3 months or as indicated. Typically, lipid concentrations normalize after dose reduction or discontinuation of the drug, as well as with diet. It is necessary to monitor a clinically significant increase in triglyceride levels, since their rise above 800 mg/dL or 9 mmol/L can be accompanied by the development of acute pancreatitis, possibly fatal. In case of persistent hypertriglyceridemia or symptoms of pancreatitis, Sotret should be discontinued. In rare cases, depression, psychotic symptoms, and very rarely, suicide attempts have been described in patients treated with Sotret. Although their causal relationship with the use of the drug has not been established, special caution should be exercised in patients with a history of depression and all patients should be monitored for the occurrence of depression during treatment with the drug, if necessary, referring them to an appropriate specialist. However, discontinuation of Sotret may not lead to the disappearance of symptoms and further observation and treatment by a specialist may be required. In rare cases, at the beginning of therapy, an exacerbation of acne is observed, which resolves within 7-10 days without adjusting the dose of the drug.

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

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

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

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

Visual acuity must 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 mucous membrane of the eyes is dry, you can use applications of a moisturizing eye ointment or an artificial tear preparation. Patients with dry conjunctiva should be monitored for possible development of keratitis.

Patients with vision complaints should be referred to an ophthalmologist and consider the advisability of discontinuing Sotret. If you are intolerant to contact lenses, you should use glasses during therapy. Exposure to sunlight and UV rays should be limited. If necessary, use sunscreen with a high protection factor of at least 15 SPF.

Rare cases of the development of benign intracranial hypertension (“pseudotumor cerebri”) have been described, incl. when combined with tetracyclines. In such patients, Sotret should be discontinued immediately.

During therapy with Sotret, inflammatory bowel disease may occur. In patients with severe hemorrhagic diarrhea, Sotret must be discontinued immediately.

Rare cases of anaphylactic reactions that occurred only after previous external use of retinoids have been described.

Severe allergic reactions dictate the need to discontinue the drug and carefully monitor the patient. Patients at high risk (with diabetes, obesity, chronic alcoholism or lipid metabolism disorders) may require more frequent laboratory monitoring of glucose and lipid levels when treated with Sotret. If diabetes is present or suspected, more frequent monitoring of glycemia is recommended.

Active ingredient

Isotretinoin

Composition

Active substance:

isotretinoin 20 mg.

Excipients: hydrogenated soybean oil – 15.30 mg, hydrogenated vegetable oil – 64.26 mg, white beeswax – 18.36 mg, disodium edetate – 0.16 mg, butylated hydroxyanisole – 0.032 mg, refined soybean oil – 201.888 mg.

Gelatin capsule: gelatin – 123.651 mg, glycerol – 64.645 mg, allura red dye – 0.198 mg, brilliant blue dye FCF – 0.011 mg, titanium dioxide – 0.495 mg, purified water – q.s., light liquid paraffin * – q.s., isopropanol * – q.s.

Edible black ink S-1-17823 – 1.5 mg.

Composition of Black Food Ink S-1-17823: shellac 45% (20% esterified) in ethanol – 0.666 mg, black iron oxide dye – 0.350 mg, isopropanol* – 0.404 mg, n-butanol* – 0.034 mg, propylene glycol – 0.030 mg, ammonium hydroxide* – 0.016 mg.

* The solvent is not present in the final product and evaporates during the production process.

Pregnancy

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

Isotretinoin is a drug with a strong teratogenic effect. If pregnancy occurs while a woman is taking isotretinoin orally (at any dose and even for a short time), there is a very high risk of giving birth to a child with developmental defects.
Sotret is contraindicated in women of childbearing age, unless the woman’s condition meets all of the following criteria:

• she must have severe acne that is resistant to conventional treatments;
• she must clearly understand and follow the doctor’s instructions;
• she must be informed by a doctor about the danger of pregnancy during treatment with Sotret, within one month after it and urgent consultation if pregnancy is suspected;
• she should be warned about the possible ineffectiveness of contraceptives;
• she must confirm that she understands the precautions;
• she must understand the need and continuously use effective methods of contraception for one month before treatment with Sotret, during treatment and for a month after its completion (see section “Interaction with other drugs”); it is advisable to use 2 different methods of contraception at the same time, including barrier;
• she must have received a negative result from a reliable pregnancy test within 11 days before starting the drug; A pregnancy test is strongly recommended monthly during treatment and 5 weeks after the end of therapy;
• she should start treatment with Sotret only on the 2-3 day of the next normal menstrual cycle;
• she must understand the need for mandatory visits to the doctor every month;
• when being treated for a relapse of the disease, she must constantly use the same effective methods of contraception for one month before starting treatment with Sotret, during treatment and for a month after its completion, as well as undergo the same reliable pregnancy test;
• she must fully understand the need for precautions and confirm her understanding and desire to use reliable methods of contraception that have been explained to her
doctor.

Use of contraception as directed above during treatment with isotretinoin should be recommended even in women who do not routinely use contraception due to infertility (except in patients who have had a hysterectomy), amenorrhea, or who report not being sexually active.

The doctor must be sure that:
• the patient suffers from severe acne (nodulocystic, conglobate acne or acne with risk of scarring); acne that does not respond to other types of therapy;
• a negative result from a reliable pregnancy test was obtained before starting 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 a barrier method, for one month before starting treatment with Sotret, during treatment and for a month after its completion;
• the patient is able to understand and fulfill all of the above requirements for contraception;
• the patient meets all of the above conditions.

Pregnancy test

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

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

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 sexual activity and previous menstrual irregularities. If indicated, a pregnancy test is performed on the day of the visit or three days before the visit to the doctor, the test results must be recorded.

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

A prescription for Sotret for a woman capable of childbearing can be issued only for 30 days of treatment; continuation of therapy requires a new prescription of the drug by a doctor. It is recommended to take a pregnancy test, write a prescription and receive the drug on the same day.
Sotret should be dispensed in a pharmacy only within 7 days from the date of issuing the prescription.

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

Contraindications

Pregnancy, breastfeeding (see section “Pregnancy and breastfeeding”), liver failure, hypervitaminosis A, severe hyperlipidemia, concomitant therapy with tetracyclines.

Hypersensitivity to the drug or its components.

Children’s age up to 12 years.

With caution
History of depression, diabetes mellitus, obesity, lipid metabolism disorders, alcoholism.

Side Effects

Most of the side effects of Sotret depend on the dose. 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. Side effects are usually reversible after dose adjustment or drug discontinuation, but some may persist after treatment is stopped.

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

Skin and its appendages: rash, itching, facial erythema/dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophy, increased proliferation of granulation tissue, persistent thinning of hair, reversible hair loss, fulminant forms of acne, hirsutism, hyperpigmentation, photosensitivity, photoallergy, easy skin trauma. At the beginning of treatment, acne may worsen and persist for several weeks.

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

Central nervous system and mental sphere: behavioral disturbances, depression, headache, increased intracranial pressure (“pseudotumor cerebri”: headache, nausea, vomiting, blurred vision, papilledema), seizures.

Sense organs: isolated cases of impaired visual acuity, photophobia, impaired dark adaptation (reduced twilight visual acuity), rarely – impaired color vision (passing after discontinuation of the drug), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, papilledema (as a manifestation of intracranial hypertension); hearing loss 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 a fatal outcome have been described. Transient and reversible increase in the activity of liver transaminases, isolated cases of hepatitis.

In many of these cases, the changes did not go beyond the normal range and returned to the initial values ​​during treatment, but in some situations there was a need 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 platelet count, accelerated ESR.

Laboratory indicators: hypertriglyceridemia, hypercholesterolemia, hyperuricemia, decreased levels of high-density lipoproteins, rarely – hyperglycemia. While taking Sotret, cases of newly diagnosed diabetes mellitus were reported. In some patients, especially those involved in intense physical activity, isolated cases of increased CK activity in the serum have been described.

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 administration of Sotret and vitamin A should be avoided.

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

Isotretinoin may reduce the effectiveness of progesterone preparations, so contraceptives containing low doses of progesterone should not be used.

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

Overdose

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

Storage conditions

In a place protected from light and moisture, at a temperature not exceeding 25 °C

Shelf life

2 years

Manufacturer

Sun Pharmaceutical Industries Ltd, India