Aknetin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACNETIN® (ACNETIN®)

Composition:

Active substance: isotretinoin;

1 capsule contains 8 mg or 16 mg of isotretinoin;

Excipients: glycerol monostearate macrogol, refined soybean oil, sorbitan oleate, gelatin, titanium dioxide (E 171), red iron oxide (E 172) (for the 8 mg dosage), yellow iron oxide (E 172) (for the 16 mg dosage), indigo carmine (E 132) (for the 16 mg dosage).

Pharmaceutical form. Capsules.

Main physicochemical properties:

8 mg capsules — gelatin capsules No. 3 with reddish-brown body and cap. The capsule contents are an orange-colored waxy paste;

16 mg capsules — gelatin capsules No. 1 with white body and green cap. The capsule contents are an orange-colored waxy paste.

Pharmacotherapeutic group.

Systemic agents for treatment of acne. ATC code D10B A01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Isotretinoin is a stereoisomer of all-trans-retinoic acid (tretinoin). The exact mechanism of action of isotretinoin has not yet been fully elucidated; however, improvement in the clinical picture of severe acne is associated with reduced sebaceous gland activity and histologically confirmed reduction in their size. In addition, isotretinoin has demonstrated anti-inflammatory effects on the skin.

Pharmacokinetics.

Efficacy. Hyperkeratosis of the epithelial cells of the hair follicle and sebaceous gland leads to desquamation of corneocytes into the gland duct and subsequent obstruction of the duct by keratin and excess sebum. This results in comedone formation, and in some cases, a secondary inflammatory process may develop. Acnetin® suppresses sebocyte proliferation and acts on acne by restoring normal cellular differentiation. Sebum is the primary substrate for the growth of Propionibacterium acnes. Reduction in sebum production suppresses bacterial colonization of the duct.

Absorption. Gastrointestinal absorption of isotretinoin is variable and linearly dependent on dose within the therapeutic dose range. Absolute bioavailability of isotretinoin has not been determined, as there is no intravenous formulation available; however, extrapolation of data from dog studies suggests very low and variable systemic bioavailability. Administration of isotretinoin with food increases its bioavailability approximately twofold compared to administration on an empty stomach.

Distribution. Isotretinoin is almost completely bound to plasma proteins (99.9%), primarily to albumins. The volume of distribution of isotretinoin in humans is unknown due to the absence of an intravenous formulation. Concentrations of isotretinoin in the epidermis are about half of those in blood plasma. Plasma concentrations of isotretinoin are approximately 1.7 times higher than in whole blood due to poor penetration of isotretinoin into erythrocytes.

Metabolism. After oral administration, three main metabolites are observed in plasma: 4-oxo-isotretinoin, tretinoin (all-trans-retinoic acid), and 4-oxo-retinoic acid. These metabolites have demonstrated biological activity in several in vitro tests. Clinical studies have shown that 4-oxo-isotretinoin contributes significantly to the therapeutic activity of isotretinoin (inhibition of sebum excretion), independently of plasma levels of isotretinoin and tretinoin. The primary metabolite is 4-oxo-isotretinoin, whose plasma concentrations at steady state are 2.5 times higher than those of the parent drug. Other metabolites, including glucuronide conjugates, are minor.

Since isotretinoin and tretinoin (all-trans-retinoic acid) are reversibly interconverted, the metabolism of tretinoin is linked to that of isotretinoin. It has been established that 20–30% of an isotretinoin dose undergoes isomerization.

Enterohepatic recirculation may play a significant role in the pharmacokinetics of isotretinoin in humans.

In vitro metabolism studies indicate that several CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. Apparently, no single isoenzyme plays a dominant role. Acnetin® and its metabolites do not have a significant effect on the activity of CYP enzyme systems.

Elimination. After oral administration of radiolabeled isotretinoin, approximately equal amounts are excreted in urine and feces. The terminal elimination half-life of unchanged drug following oral administration in patients with acne averages 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin ranges from 7 to 39 hours.

Isotretinoin belongs to natural (physiological) retinoids. Endogenous retinoid concentrations return to baseline approximately two weeks after discontinuation of Acnetin®.

Pharmacokinetics in special clinical situations. Since isotretinoin is contraindicated in patients with impaired liver function, pharmacokinetic data in this patient group are limited.

Renal insufficiency does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.

Clinical characteristics.

Indications.

Severe forms of acne (particularly nodular and conglobate acne, acne with a tendency to persistent scarring) that are unresponsive to standard treatment methods (systemic antibacterial therapy, topical treatment).

Prior to initiating isotretinoin treatment, two independent physicians prescribing the medicinal product must agree that no other appropriate and effective treatment is available for patients under 18 years of age (see section "Paediatric population").

Contraindications.

Pregnancy and breastfeeding. Should not be used in women of childbearing potential unless all requirements of the "Pregnancy Prevention Programme" are fulfilled (see below). Hypersensitivity to isotretinoin or to any of the excipients; hepatic failure; severe hyperlipidaemia; hypervitaminosis A; concomitant therapy with tetracyclines. Since Aknetin® contains soybean oil, the product is contraindicated in patients with known allergy to peanuts and soy.

Interaction with other medicinal products and other forms of interaction.

Due to the potential for increased symptoms of hypervitaminosis A, concomitant administration of Aknetin® and vitamin A should be avoided.

Cases of benign intracranial hypertension (pseudotumour cerebri) have been reported with concomitant use of isotretinoin and tetracyclines. Therefore, concomitant use with tetracyclines should be avoided (see sections "Contraindications", "Special precautions").

Combined use with topical keratolytic or exfoliative acne treatments is contraindicated due to the potential for increased local irritation (see section "Special precautions").

Special precautions for use.

Teratogenic effects.

The medicinal product Aknetin® is a potent human teratogen and induces a high frequency of severe and life-threatening congenital malformations.

The medicinal product Aknetin® is absolutely contraindicated:

• in pregnant women;
• in women of reproductive potential unless all conditions of the "Pregnancy Prevention Program" are met (see below).

Pregnancy Prevention Program.

This medicinal product is TERATOGENIC

Aknetin® is contraindicated in women of reproductive potential except in cases where all the following conditions are met:

• the woman has been diagnosed with severe acne (nodular and conglobate acne, acne with a tendency to persistent scarring) that is unresponsive to standard treatment (systemic antibiotic therapy, topical treatment) (see section "Contraindications");
• the woman's potential for becoming pregnant has been assessed;
• the woman understands the teratogenic risk of the drug;
• the woman understands the necessity of mandatory monthly physician visits;
• the woman understands and agrees to the necessity of using effective contraception: continuously for 1 month before starting Aknetin®, during treatment, and for 1 month after treatment ends. At least one highly effective method of contraception (whose effectiveness does not depend on the patient, such as an intrauterine device or implant) or two complementary user-dependent methods of contraception (e.g., oral contraceptives and condoms) should be used for at least 1 month before starting Aknetin®, during treatment, and for 1 month after treatment ends;
• in each individual case, the choice of contraceptive method takes into account individual circumstances, and the patient is involved in the discussion to ensure her engagement and correct use of the selected methods;
• even in cases of amenorrhea, the woman uses reliable contraception;
• the woman confirms that she understands the nature of preventive measures;
• the woman is informed about the danger of pregnancy during Aknetin® treatment and understands the need to consult immediately if pregnancy is suspected or confirmed;
• the woman understands the necessity and agrees to regularly perform pregnancy tests before, during, and 5 weeks after treatment;
• the woman confirms that she is aware of the risks associated with isotretinoin use and the necessity of preventive measures.

The use of contraceptive measures according to the above recommendations during isotretinoin treatment should be recommended even for sexually inactive women, except when the physician has sufficient grounds to believe that the risk of pregnancy is absent.

The physician must be certain that:

• the patient is able to understand and comply with all the above-mentioned pregnancy prevention requirements;
• the patient is familiar with the above-mentioned conditions;
• the patient understands the necessity of continuous and correct use of at least one highly effective method of contraception (whose effectiveness does not depend on the patient, such as an intrauterine device or implant) or two complementary methods of contraception (whose effectiveness depends on the user, e.g., oral contraceptives and condoms);
• the patient confirms that she is aware of the above-mentioned conditions;
• a negative result of a reliable pregnancy test has been obtained before starting the drug, during treatment, and 1 month after therapy ends. The date and results of the pregnancy test must be documented.

If pregnancy occurs in a woman receiving isotretinoin treatment, therapy should be discontinued immediately, and the patient should be referred to a physician specialized in or experienced in teratology for evaluation and counseling. If pregnancy occurs after completion of treatment, there remains a risk of severe and serious congenital fetal abnormalities. This risk persists until the drug is completely eliminated from the body, which occurs within one month after treatment ends.

Pregnancy prevention.

Patients must be informed about contraceptive methods. If they are not using effective contraceptive methods, the physician should provide appropriate recommendations. If the treating physician is unable to provide such information, the patient should be referred to a physician of appropriate specialization.

As a mandatory minimum, women of reproductive potential should use at least one highly effective method of contraception (whose effectiveness does not depend on the user) or two complementary methods of contraception (whose effectiveness depends on the user). Contraceptive methods should be used for at least 1 month before starting Aknetin®, during treatment, and for 1 month after treatment ends, even in patients with amenorrhea. When choosing a contraceptive method in each individual case, individual circumstances should be evaluated, and the patient should be involved in the discussion to ensure her engagement and correct use of the selected methods.

Pregnancy testing.

According to current practice, a pregnancy test with a minimum sensitivity of 25 mIU/mL should be performed under medical supervision during the first 3 days of the menstrual cycle.

Before starting treatment.

At least one month after starting contraception and shortly (preferably a few days) before the first dose of the drug, the patient should undergo a pregnancy test under medical supervision to confirm she is not pregnant at the start of isotretinoin therapy. The specialist should record the test results.

In patients with irregular menstrual cycles, the timing of the pregnancy test depends on sexual activity. The test should be performed 3 weeks after unprotected intercourse. The physician should inform the patient about contraceptive methods.

Aknetin® may only be prescribed to patients who have been using effective contraception for at least 1 month. The test must confirm that the patient is not pregnant at the start of isotretinoin therapy.

During treatment.

The patient should visit the physician regularly, ideally once a month. The need for monthly pregnancy testing is determined according to local practice and taking into account sexual activity and the history of recent menstrual cycles (abnormal menstruation, lack of regularity, or amenorrhea). If indicated, the pregnancy test should be performed on the day of the visit or up to 3 days before the visit.

End of treatment.

One month after completing treatment, a final pregnancy test is performed to exclude pregnancy.

Precautions regarding prescription and distribution of the medicinal product.

Ideally, prescriptions for Aknetin® for women of reproductive potential should be issued for a duration of 30 days only; continuation of treatment requires a new prescription from the physician.

Ideally, pregnancy testing, prescription issuance, and drug dispensing should occur on the same day. The dispensing of Aknetin® at the pharmacy should occur no later than 7 days after the prescription is issued. This monthly monitoring allows for regular pregnancy testing and ensures that the patient is not pregnant before the next treatment cycle.

For patients whom the prescribing physician considers to have strong grounds indicating absence of pregnancy risk, after stable use of isotretinoin without pregnancy occurrence (after the first 1–3 months), subsequent prescriptions may be issued for a treatment period longer than 30 days (up to 12 weeks).

Male patients.

Available data indicate that exposure of the drug from semen and seminal fluid of men who have taken Aknetin® is insufficient to cause teratogenic effects in women. Men should prevent others, especially women, from using the drug. Patients should be reminded not to give their prescribed medication to other individuals, especially women.

Additional warnings.

Patients should be warned never to give this medicinal product to others and to return all unused capsules to their pharmacist after treatment ends. Patients must not donate blood during treatment and for 1 month after completing isotretinoin therapy due to the potential risk to fetuses of pregnant women receiving donor blood.

Educational materials.

To help physicians, pharmacists, and patients avoid the risk of Aknetin® affecting the fetus, the manufacturer provides educational materials aimed at preventing the teratogenic effects of the drug, recommendations on contraception use before starting therapy, and recommendations on the necessity of pregnancy testing.

Complete information on teratogenic risk and strict adherence to pregnancy prevention measures is contained in the "Pregnancy Prevention Program," which must be provided to all patients—both male and female.

Additionally, the educational materials include warnings about potential risks of isotretinoin for mental health and sexual function.

Psychiatric disorders.

Depression, depression with aggravation, anxiety, aggression tendency, mood changes, psychotic symptoms, suicidal thoughts, suicide attempts, and suicide have been reported in patients receiving Aknetin® (see section "Adverse reactions").

Patients and, if appropriate, their parents or guardians should be counseled before prescribing isotretinoin and, ideally, before any referral to a physician who may consider isotretinoin treatment, regarding the risk of psychiatric disorders.

Before starting isotretinoin therapy, all patients should undergo a mental health assessment and be regularly monitored during treatment for the development or worsening of psychiatric disorders. Particular caution is needed in patients with a history of depression. If necessary, appropriate treatment for psychiatric disorders should be prescribed. Discontinuation of Aknetin® may not resolve psychiatric symptoms—such patients require further monitoring by specialists.

Awareness of family members or friends may be helpful in detecting psychiatric disturbances.

Sexual disorders.

The use of isotretinoin may be associated with sexual dysfunction (see section "Adverse reactions"). Reports of prolonged sexual dysfunction have been received, where symptoms persisted despite discontinuation of isotretinoin.

Patients and, if appropriate, their parents or guardians should be counseled before prescribing the drug, and ideally before any referral to a physician who may consider isotretinoin treatment, regarding the risk of sexual dysfunction with isotretinoin use. The patient's age and sexual maturity should be considered when choosing the most appropriate approach to such counseling, including the possibility of discussion without the presence of parents or guardians, if appropriate.

Before starting isotretinoin therapy, all patients should be asked about symptoms of sexual dysfunction, and patients should be monitored during treatment for the emergence of new sexual disorders.

Disorders of the skin and subcutaneous tissue.

In isolated cases, acne may worsen at the beginning of therapy, which usually resolves within 7–10 days without dose adjustment.

Intense exposure to sunlight or UV radiation should be avoided. If sun protection is needed, a sunscreen with a high protection factor (at least SPF 15) should be used.

Deep chemical peels and laser treatments should not be performed during Aknetin® treatment and for 5–6 months after treatment due to a high risk of hypertrophic scarring in atypical areas and the risk of hyper- and hypopigmentation in treated areas. During Aknetin® treatment and for 6 months after treatment, waxing should not be performed due to the risk of epidermal detachment.

Concomitant use of Aknetin® with topical keratolytic or exfoliating agents for acne treatment should be avoided due to the possibility of increased local irritation (see section "Interaction with other medicinal products and other forms of interaction").

Patients receiving Aknetin® are advised to use moisturizing ointments or creams for the body and lip balm to reduce skin and lip dryness at the beginning of treatment.

In the post-marketing period, severe skin reactions (exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Since these reactions are difficult to distinguish from other possible skin reactions (see section "Adverse reactions"), patients should be warned about the signs and symptoms of these conditions and closely monitored for skin reactions. If severe skin reactions are suspected, isotretinoin therapy should be discontinued.

Allergic reactions.

Anaphylactic reactions have been rarely reported, sometimes after prior topical use of retinoids. Allergic skin reactions have been infrequently reported. Serious cases of allergic vasculitis, often with purpura (bruising and red spots), as well as non-cutaneous manifestations, are known. Serious allergic reactions require therapy interruption and careful patient monitoring.

Disorders of the visual organs.

Dry eyes, corneal clouding, impaired night vision, and keratitis usually resolve after discontinuation of treatment. Cases of persistent dry eyes after treatment cessation have been reported. Moisturizing eye ointments or artificial tear preparations may be used to prevent dry eyes. In cases of intolerance to contact lenses, glasses should be used during treatment.

In some patients, reduced night vision may occur, sometimes suddenly (see section "Ability to influence reaction rate when driving or operating machinery"). Patients with vision complaints should be referred to an ophthalmologist, and discontinuation of the drug should be considered.

Disorders of the musculoskeletal system and connective tissue.

Muscle and joint pain and increased serum creatine phosphokinase levels may occur during Aknetin® use, especially with intense physical exertion (see section "Adverse reactions"). In some cases, this may progress to rhabdomyolysis, a life-threatening condition.

After several years of isotretinoin use for treating keratinization disorders at very high doses, bone changes such as premature closure of epiphyseal growth plates, hyperostosis, ligament and tendon calcification have developed. Daily doses, treatment duration, and total cumulative doses in these patients generally exceeded those recommended for acne treatment.

Cases of sacroiliac joint inflammation (sacroiliitis) have been reported in patients taking isotretinoin. To differentiate sacroiliitis from other causes of back pain in patients with clinical signs of sacroiliitis, further evaluation, including imaging studies such as MRI, may be necessary. In post-marketing cases, sacroiliitis resolved after discontinuation of Aknetin® and initiation of appropriate treatment.

Benign intracranial hypertension.

Cases of benign intracranial hypertension have been described, sometimes associated with concomitant use of tetracyclines (see sections "Contraindications," "Interaction with other medicinal products and other forms of interaction"). Symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances, and papilledema. Patients who develop benign intracranial hypertension should discontinue the drug immediately.

Hepatobiliary disorders.

Liver enzymes should be monitored before treatment, 1 month after initiation, and then every 3 months, unless clinical indications require more frequent monitoring. Transient and reversible increases in liver transaminase levels have been observed, mostly within normal ranges, returning to baseline levels during treatment. If transaminase levels exceed normal values, the drug dose should be reduced or discontinued.

Renal impairment.

Renal function impairment or renal failure does not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin may be administered to patients with renal impairment. However, it is recommended to start with a low dose and titrate to the maximum tolerated dose (see section "Dosage and administration").

Lipid metabolism.

Serum lipid levels should be measured fasting (before treatment, 1 month after initiation, then every 3 months, unless clinical indications require more frequent monitoring). Elevated serum lipid levels usually normalize after dose reduction or discontinuation of the drug, as well as with dietary adherence. Isotretinoin use is associated with increased triglyceride levels. Isotretinoin should be discontinued in cases of uncontrolled hyperlipidemia or symptoms of pancreatitis.

Elevated triglyceride levels above 8 mg/L or 9 mmol/L may be accompanied by acute pancreatitis, possibly with fatal outcome.

Gastrointestinal disorders.

Inflammatory bowel disease (including regional ileitis) may develop during isotretinoin treatment. Patients who develop severe (hemorrhagic) diarrhea should immediately discontinue the drug.

High-risk groups.

Patients with diabetes, obesity, alcoholism, or lipid metabolism disorders may require more frequent monitoring of serum glucose and/or lipid levels during isotretinoin treatment. Increased fasting blood glucose and new-onset diabetes have been reported during isotretinoin therapy.

Fructose intolerance.

The medicinal product contains sorbitan oleate. This medicinal product is not recommended for patients with hereditary fructose intolerance.

Use during pregnancy or breastfeeding.

Pregnancy.

Pregnancy is absolutely contraindicated for the use of Aknetin® (see section

"Contraindications"). Women of reproductive potential must use effective contraception during treatment and for one month after treatment. If pregnancy occurs while a woman is taking Aknetin®, despite preventive measures, or within one month after therapy ends, there is a very high risk of giving birth to a child with severe and serious developmental abnormalities.

Fetal abnormalities associated with isotretinoin include central nervous system disorders (hydrocephalus, cerebellar development defects/anomalies, microcephaly), facial malformations ("cleft palate"), external ear anomalies (absent external ear, small or absent external auditory canal), eye abnormalities (microphthalmia), heart and vascular anomalies (conotruncal heart defects such as tetralogy of Fallot, transposition of the great vessels, septal defects), thymus and parathyroid gland anomalies. Additionally, the risk of spontaneous abortions is increased.

If pregnancy occurs in a woman undergoing isotretinoin treatment, therapy should be discontinued and the patient should be referred to a physician specialized in and experienced in teratology for evaluation and counseling.

Breastfeeding.

Due to the high lipophilicity of isotretinoin, there is a high likelihood that it passes into breast milk. Because of possible adverse effects in the infant due to the drug's action via maternal milk, isotretinoin is contraindicated in women during breastfeeding (see section "Contraindications").

Fertility.

If a man takes isotretinoin at therapeutic doses, it does not affect sperm count, motility, or morphology and does not endanger embryo formation and development.

Ability to influence reaction rate when driving or operating machinery.

The medicinal product may potentially affect the ability to drive vehicles or operate machinery. During treatment and, in rare cases, after treatment, some patients have experienced reduced twilight vision acuity (see sections "Adverse reactions," "Special precautions for use"). Since in some individuals the onset of these phenomena may be sudden, patients should be informed about the possibility of this problem and advised to exercise caution when driving or operating machinery. Very rarely, cases of somnolence, dizziness, and visual disturbances have been reported. Patients should be warned that if these symptoms occur, they should not drive, operate machinery, or engage in any other activity that could endanger themselves or others.

Method of Administration and Dosage.

Standard Dosage Regimen.

Isotretinoin treatment must be prescribed and supervised only by a physician experienced in the use of systemic retinoids for the treatment of severe acne and fully aware of the risks associated with retinoid therapy and the requirements for patient monitoring.

Acnetin**®** should be prescribed to adults and children aged 12 years and older, starting at a dose of 0.4 mg/kg per day. Capsules should be taken with food once or twice daily.

If a dose is missed, do not take a double dose of the medication!

The therapeutic response to Acnetin**®** as well as adverse effects are dose-dependent and vary in intensity. Therefore, individual dose adjustment during treatment is required. For most patients, the dose ranges from 0.4 to 0.8 mg/kg per day.

A transient exacerbation of the disease is often observed at the beginning of treatment. The efficacy of treatment and side effects vary among patients; therefore, after 4 weeks of therapy, the dose should be individually adjusted for adults to between 0.1 and 1 mg/kg per day. The maximum daily dose of 1 mg/kg may be prescribed only for a limited period.

The usual course of treatment lasts from 16 to 24 weeks. When evaluating treatment outcomes, it should be remembered that the drug's effect often continues after discontinuation of therapy. Therefore, a repeat course should not be initiated earlier than 8 weeks after the end of the previous course.

For most patients, a single course of treatment is sufficient to achieve clearance of acne. In case of confirmed relapse, a repeat course of isotretinoin may be considered. The dose for retreatment should be determined according to the above recommendations.

For patients who poorly tolerate the recommended doses, treatment may be continued at a lower dose, which should be accompanied by an extension of treatment duration and may accordingly increase the risk of relapse. For such patients, the treatment course should be continued using the highest tolerable dose.

Dosage in Special Situations.

Patients with Renal Impairment. In patients with severe renal impairment, treatment should be initiated at a lower dose (e.g., 10 mg/day), then gradually increased to 1 mg/kg/day or to the maximum tolerated dose (see section "Special Precautions").

Patients with Intolerance. In patients who develop severe intolerance to the recommended dose, treatment may be continued at a lower dose. In such cases, treatment duration will be longer and the risk of relapse higher. To achieve maximum efficacy, the highest tolerable dose should be used.

Children.

The drug should not be used for the treatment of acne in the prepubertal period and is not recommended for children under 12 years of age, as safety and efficacy in this age group have not been established.

Prior to initiating isotretinoin treatment, two independent physicians prescribing the drug must agree that no other appropriate and effective treatment options are available for patients under 18 years of age (see section "Indications").

Overdose.

Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretinoin is low, signs of hypervitaminosis A may occur in case of accidental overdose. Symptoms of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and itching. Symptoms following accidental or intentional overdose are likely to be similar. These symptoms are reversible and resolve without treatment.

Adverse Reactions

Some adverse effects of isotretinoin are dose-dependent. Adverse reactions are usually reversible after dose adjustment or discontinuation of the drug, but some may persist after treatment cessation. The most commonly reported symptoms during isotretinoin use include dryness of the skin and mucous membranes, including lips (cheilitis), nasal mucosa (epistaxis), eyes (conjunctivitis).

The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (≤1/10,000), and frequency not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections: very rare — gram-positive bacterial infections of the skin and mucous membranes.

Blood and lymphatic system disorders: very common — anaemia, increased erythrocyte sedimentation rate, thrombocytopenia, thrombocytosis; common — neutropenia; very rare — lymphadenopathy.

Immune system disorders: uncommon — allergic reactions of the skin, anaphylactic reactions, hypersensitivity reactions.

Metabolism and nutritional disorders: very rare — diabetes mellitus, hyperuricaemia.

Psychiatric disorders: uncommon — aggression, anxiety, mood changes; very rare — behavioural disturbances, psychotic disorders; frequency not known — depression, worsening of depression, suicide, suicide attempts, suicidal ideation.

Nervous system disorders: common — headache; very rare — benign intracranial hypertension, seizures, somnolence, dizziness.

Eye disorders: very common — blepharitis, conjunctivitis, dry eyes, eye irritation; very rare — blurred vision, cataract, colour vision defects, intolerance to contact lenses, corneal opacity, reduced twilight vision, keratitis, optic disc swelling (as manifestation of benign intracranial hypertension), photophobia, visual disturbances.

Ear and labyrinth disorders: very rare — hearing impairment.

Vascular disorders: very rare — vasculitis (e.g., Wegener's granulomatosis, allergic vasculitis).

Respiratory, thoracic and mediastinal disorders: common — epistaxis, nasal dryness, nasopharyngitis; very rare — bronchospasm (especially in patients with asthma), dysphonia.

Gastrointestinal disorders: very rare — colitis, ileitis, throat dryness, gastrointestinal haemorrhage, haemorrhagic diarrhoea, inflammatory bowel disease, nausea, pancreatitis. Cases of severe diarrhoea have also been reported (see section "Special precautions").

Hepatobiliary disorders: very common — increased transaminase levels (see section "Special precautions"); very rare — hepatitis.

Skin and subcutaneous tissue disorders: very common — cheilitis, dermatitis, dry skin, localized desquamation, pruritus, erythematous rash, skin fragility (risk of injury due to friction); uncommon — alopecia; very rare — fulminant forms of acne, acne flare (acne hyperemia), erythema (face), exanthema, hair disorders, hirsutism, onychodystrophy, paronychia, photosensitization, pyogenic granuloma, skin hyperpigmentation, increased sweating; frequency not known — erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: very common — arthralgia, myalgia, back pain (especially in children and adolescents); very rare — arthritis, calcinosis (calcification of ligaments and tendons), premature closure of epiphyseal growth plates, exostosis, hyperostosis, decreased bone density, tendinitis; frequency not known — rhabdomyolysis, sacroiliitis.

Renal and urinary disorders: very rare — glomerulonephritis; frequency not known — urethritis.

Reproductive system and breast disorders: frequency not known — sexual dysfunction, including erectile dysfunction and decreased libido, gynecomastia, vulvovaginal dryness, orgasmic disturbances, genital hypoaesthesia.

General disorders: very rare — granulation tissue formation (increased formation), fatigue.

Investigations: very common — hypertriglyceridaemia, decreased high-density lipoprotein levels; common — hypercholesterolaemia, hyperglycaemia, haematuria, proteinuria; very rare — increased blood creatine phosphokinase levels.

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: http://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Packaging.

10 capsules in a blister; 3 blisters in a pack.

Prescription status. Prescription only.

Manufacturer.

S.M.B. Technologies S.A.

Manufacturer's address.

Zoning Industriel - Rue du Parc Industriel 39, Marche-en-Famenne, 6900, Belgium.

Marketing Authorization Holder.

Jadran-Galenski Laboratorij d.d.

Address of Marketing Authorization Holder.

Svilno 20, 51000 Rijeka, Croatia.