Aknecutan, 16 mg capsules 30 pcs

Isotretinoin is the stereoisomer of fully transretinoic acid (tretinoin).

The exact mechanism of action of isotretinoin has not yet been identified, but it has been established that improvement in the clinical picture of severe acne is associated with suppression of sebum activity and a histologically confirmed reduction in its size. Sebum is the main substrate for Propionibacterium acnes growth, so a decrease in sebum formation suppresses bacterial colonization of the ductus.

Acnekutan suppresses the proliferation of sebocytes and acts on acne by restoring the normal process of cell differentiation and stimulates regeneration processes.

In addition, the anti-inflammatory effect of isotretinoin on the skin has been proven.

Pharmacokinetics

. After oral administration, absorption is variable and the bioavailability of Acnekutan is low and variable – driven by the proportion of dissolved isotretinoin in the drug, and may also increase when the drug is taken with food. In patients with acne, maximum plasma concentrations (Cmax) in equilibrium after isotretinoin 80 mg ingested on an empty stomach were 310 ng/mL (range 188-473 ng/mL) and were reached after 2-4 hours. Plasma concentrations of isotretinoin were 1.7 times higher than blood concentrations due to poor isotretinoin penetration into erythrocytes. Binding with plasma proteins (mainly with albumin) is 99.9%.

The equilibrium blood concentrations (Css) of isotretinoin in patients with severe acne who received 40 mg of the drug twice daily ranged from 120 to 200 ng/ml. Concentrations of 4-oxo-isotretinoin (the main metabolite) in these patients were 2.5 times higher than those of isotretinoin.

The concentration of isotretinoin in epidermis is 2 times lower than in serum. It is metabolized with the formation of 3 main biologically active metabolites – 4-oxo-isotretinoin (main), tretinoin (fully transretinoic acid) and 4-oxo-retinoin, as well as less significant metabolites including also glucuronides. Since in vivo isotretinoin and tretinoin 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. Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans.

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

The terminal phase elimination half-life for isotretinoin averages 19 hours. The terminal phase elimination half-life for 4-oxo-isotretinoin averages 29 hours.

Isotretinoin is excreted by the kidneys and with the bile in approximately equal amounts. It is referred to natural (physiological) retinoids. Endogenous concentrations of retinoids are restored about 2 weeks after the end of the drug.

Pharmacokinetics in special clinical cases

Because data on the pharmacokinetics of the drug in patients with impaired liver function are limited, isotretinoin is contraindicated in this group of patients. Renal failure of mild to moderate severity does not affect the pharmacokinetics of isotretinoin.

Indications

Common acne (vulgar), Severe forms of acne

Severe forms of acne (nodular-cystic, conglobate, acne with the risk of scarring).

Acnees which are not amenable to other kinds of therapy.

Active ingredient

Isotretinoin

Composition

Auxiliary substances:

Helucyr® 50/13 (mixture of stearic acid polyethylene oxide and glycerol esters) – 192, 00 mg;

purified soybean oil – 104.00 mg;

Span 80® (sorbitan oleate – mixed esters of oleic acid and sorbitol) – 16.00 mg.

Capsule composition:

corpus:

gelatin,

titanium dioxide (E171),

caps:

gelatin,

titanium dioxide (E171),

dye.

How to take, the dosage

Orally, preferably with meals, 1 -2 times a day.

The therapeutic efficacy of Acnekutan and its side effects are dose-dependent and vary from patient to patient. This makes it necessary to individually adjust the dose during treatment.

The initial dose of Acnekutan is 0.4 mg/kg per day, in some cases up to 0.8 mg/kg per day. In severe forms of the disease or with torso acne, a dose of up to 2 mg/kg per day may be required.

The optimal cumulative course dose is 100-120 mg/kg per day. Complete remission is usually achieved in 16-24 weeks. If the recommended dose is poorly tolerated, treatment can be continued in a lower dose, but for a longer time. In most patients, acne completely disappears after a single course of treatment.

In case of relapse, a second course of treatment may be given at the same daily and cumulative dose. A repeat course is not prescribed until 8 weeks after the first course, because improvement may be delayed.

In severe chronic renal failure, the starting dose should be reduced to 8 mg/day.

Interaction

Tetracycline antibiotics, GCS reduce the effectiveness. Concomitant use with drugs that increase photosensitivity (including sulfonamides, tetracyclines, thiazide diuretics) increases the risk of sunburn.

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

Isotretinoin may weaken the effectiveness of progesterone preparations, so contraceptives containing low-dose progesterone should not be used.

The combined use with topical keratolytics for the treatment of acne is not recommended because of the possible increase in local irritation. Because tetracyclines increase the risk of increased intracranial pressure, concomitant use with isotretinoin is contraindicated.

Special Instructions

It is recommended that liver function and liver enzymes be monitored before treatment, 1 month after initiation, and then every 3 months or as indicated. Transient and reversible increases in liver transaminases have been noted, in most cases within normal limits. If hepatic transaminase levels exceed the norm, the drug dose should be reduced or discontinued. 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.

Lipid concentrations usually normalize after dose reduction or discontinuation of the drug, as well as with diet. Clinically significant increases in triglyceride levels should be controlled, since elevations greater than 800 mg/dL or 9 mmol/L can be accompanied by the development of acute pancreatitis, possibly with a fatal outcome.

In case of persistent hypertriglyceridemia or symptoms of pancreatitis, Aknekutan should be discontinued. In rare cases, depression, psychotic symptoms and very rarely suicidal attempts have been described in patients who received Aknecutan. Although their causal relationship to 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 depression during treatment with the drug, referring them to the appropriate specialist if necessary. However, discontinuation of Aknecutan may not lead to disappearance of symptoms and further monitoring and treatment by a specialist may be necessary.

In rare cases, acne worsens at the start of therapy and resolves within 7-10 days without adjusting the dose of the drug.

When prescribing the drug to any patient, a careful assessment of the possible benefit to risk ratio should be made beforehand.

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

Accentricutane may cause muscle and joint pain and an increase in serum creatinine phosphokinase, which may be accompanied by decreased tolerance to vigorous physical activity.

Deep chemical dermoabrasion and laser treatment should be avoided in patients receiving Acknekutan and for 5-6 months after treatment termination because of the possibility of increased scarring in atypical sites and the occurrence of hyper- and hypopigmentation. During treatment with Accecutane and for 6 months after treatment, wax applications should not be performed due to the risk of epidermal detachment, scarring, and dermatitis.

Because some patients may have decreased night vision acuity, which sometimes persists after therapy ends, patients should be informed about the possibility of this condition, recommending caution when driving at night. The state of visual acuity should be closely monitored. Conjunctival dryness, corneal opacity, worsening of night vision and keratitis usually disappear after discontinuation of the drug. If the mucous membrane of the eyes is dry, applications of moisturizing eye ointment or artificial tears may be used. Patients with dry conjunctiva should be monitored for possible keratitis. Patients with visual complaints should be referred to an ophthalmologist and consideration should be given to the appropriateness of discontinuing Aknecutan. If contact lenses are intolerant, eyeglasses should be used for the duration of therapy. Exposure to solar insolation and UV therapy should be limited. If necessary, sunscreen with a high SPF value of at least 15 should be used.

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

Rare cases of anaphylactic reactions have been described that occurred only after previous 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 Aknecutan. If diabetes is present or suspected, more frequent glycemic determination is recommended.

Patients with diabetes are recommended to have more frequent blood glucose monitoring.

During treatment, caution should be exercised when driving and engaging in other potentially hazardous activities that require increased concentration and quick psychomotor reactions (when taking the first dose).

Blisters-10-N2, N3, N5, N6, N9, N10; blisters-14-N1, N2, N4, N7 in a carton pack, together with the instructions for use.

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Contraindications

Pregnancy, established and planned (teratogenic and embryotoxic effects possible), lactation, hepatic insufficiency, hypervitaminosis A, marked hyperlipidemia, concomitant therapy with tetracyclines.

Hypersensitivity to the drug or its components. Acnecutane is not indicated for the treatment of puberty acne and is not recommended for use in children under 12 years of age.

With caution
Diabetes mellitus, depression in anamnesis, obesity, lipid metabolism disorders, alcoholism.

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Side effects

Most side effects are dose-dependent. Usually the side effects are reversible after adjusting the dose or cancelling the drug, but some may persist after stopping treatment. Symptoms associated with hypervitamin A: dry skin, mucous membranes, including lips (cheilitis), nasal cavity (bleeding), larynx and pharynx (hoarseness of voice), eyes (conjunctivitis, reversible corneal clouding and contact lens intolerance).

The skin and its appendages: Palms and soles skin flaking, rash, itching, facial erythema/dermatitis, sweating, pyogenic granuloma, paronychia, onychodystrophies, increased granulation tissue overgrowth, persistent hair thinning, reversible hair loss, fulminant acne, hirsutism, hyperpigmentation, photosensitivity, mild skin trauma. At the beginning of treatment, acne exacerbation may occur and persist for several weeks.

Muscular system: muscle pain with or without increase in serum CPK levels, joint pain, hyperostosis, arthritis, calcification of ligaments and tendons, tendinitis.

Central nervous system and mental system: excessive fatigue, headache, increased intracranial pressure (“pseudotumor of the brain”: headache, nausea, vomiting, visual disturbances, optic nerve edema), seizures, rarely – depression, psychosis, suicidal thoughts. Sensory organs: xerophthalmia, isolated cases of visual acuity disorders, photophobia, dark adaptation disorders (decreased acuity of twilight vision), rare – color vision disorders (passing after drug withdrawal), lenticular cataract, keratitis, blepharitis, conjunctivitis, eye irritation, optic neuritis, optic nerve edema (as manifestation of intracranial hypertension); hearing disorders at certain sound frequencies, difficulty in wearing contact lenses.

Gastrointestinal tract: dry mucous membrane of the mouth, bleeding from the gums, inflamed gums, nausea, diarrhea, inflammatory bowel disease (colitis, ileitis), bleeding; pancreatitis (especially with concomitant hypertriglyceridemia above 800 mg/dL). Rare cases of fatal pancreatitis 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 discontinue Acknekutan.

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 level of high-density lipoproteins, rarely – hyperglycemia. Cases of newly diagnosed diabetes mellitus have been reported during administration of Aknecutan. In some patients, especially those engaged in vigorous physical activity, isolated cases of increased serum CPK activity have been described.

The immune system: local or systemic infections caused by Gram-positive pathogens (Staphylococcus aureus).

Others: lymphadenopathy, hematuria, proteinuria, vasculitis (Wegener’s granulomatosis, allergic vasculitis), systemic hypersensitivity reactions, glomerulonephritis.

Teratogenic and embryotoxic effects: Congenital deformities -hydro- and microcephaly, underdevelopment of cranial nerves, microphthalmia, malformations of the CPS, parathyroid glands, skeletal formation disorders – underdevelopment of finger phalanges, skull, cervical vertebrae, femur, ankles, forearm bones, facial skull, cleft palate, low positioning of the auricles, underdevelopment of the auricles, underdevelopment or complete absence of the external auditory canal, herniation of the brain and spinal cord, bone fusions, fusion of fingers and toes, developmental disorders of the thymus gland; perinatal fetal death, premature birth, miscarriage), premature closure of epiphyseal growth zones; in experiments on animals – pheochromocytoma.

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Overdose

In case of an overdose, signs of hypervitaminosis A may appear.

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

Pregnancy use

Pregnancy is an absolute contraindication for Acknecutan therapy. If pregnancy occurs, despite the warnings, during treatment or within .a month after the end 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 pregnancy occurs while a woman is taking isotretinoin orally (at any dose, even for short periods of time), there is a very high risk that the baby will be born with malformations.

Acnecutan is contraindicated in women of childbearing age unless the woman’s condition 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 warned of the possible failure of contraception;
• she must confirm that she understands the nature of the precautions;
• she must understand the need and continually use effective contraception for one month before, during and one month after treatment with Accecutane (see She must have a negative, reliable pregnancy test within 11 days before starting the drug; and two different contraceptive methods, including barrier contraception, should be used concurrently; a pregnancy test is strongly recommended monthly during treatment and 5 weeks after the end of therapy;
• she should not begin treatment with Accecutane until day 2-3 of her next normal menstrual cycle;
• she should understand the need for mandatory visits to the doctor every month;
• when treated for a recurrence of the disease, she should use the same effective contraceptive methods continuously for one month before starting treatment with Accecutane, during treatment and for one month after it ends, and undergo the same reliable pregnancy test;
• she must fully understand the need for precautions and confirm her understanding and willingness to use reliable contraceptive methods as explained to her by her doctor.

The use of contraception according to the above guidelines during treatment with isotretinoin should be recommended even for women who would 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;
• The patient is using at least 1, preferably 2, effective methods of contraception, including a barrier method, within one month before starting treatment with Acnecutan, during treatment, and within one month after treatment ends;
• The patient is able to understand and meet all of the above contraceptive requirements for pregnancy;
• 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 mME/ml on the first 3 days of the menstrual cycle:

Before starting therapy:

• To rule out possible pregnancy before starting contraception, the result and date of the initial pregnancy test should 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 physician should inform the patient about the contraceptive methods.
• The pregnancy test is performed on the day of prescription of Aknecutan 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 therapy with Acnecutan.

While on therapy:

• The patient must see a 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, a pregnancy test is performed on the day of the visit or three days before the visit and the test results must be recorded.

Ending therapy:

• Five weeks after therapy ends, a test is performed to rule out pregnancy.

Acnecutane prescription for a woman who is fertile can only be prescribed for 30 days of treatment, continuation of therapy requires a new prescription by the doctor. It is recommended that the pregnancy test, prescription and receipt of the drug be done on the same day.

Acnecutan should only be dispensed at the pharmacy within 7 days of the prescription.

Similarities

Roaccutane, Retinoic ointment, Retasol, Sotret