Roaccutan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ROACCUTANE®

Composition:

Active substance: isotretinoin;

1 capsule contains 10 mg or 20 mg of isotretinoin;

Excipients: beeswax yellow, hydrogenated soybean oil, partially hydrogenated soybean oil, refined soybean oil;

capsule shell: gelatin, glycerol (85%), dry substance Carion 83 (sorbitol (E 420), mannitol (E 421), hydrolyzed hydrogenated starch), titanium dioxide (E 171), iron oxide red (E 172), printing ink.

Dosage form. Capsules.

Main physicochemical properties:

Capsules 10 mg: oval, opaque capsules of brown-red color, with clear imprint «ROA 10» on the surface; capsule length 8.3–10.7 mm, diameter 5.3–7.7 mm; capsule contents — homogeneous dark yellow suspension;

Capsules 20 mg: oval, opaque capsules, one half brown-red in color, the other half white, with clear imprint «ROA 20» on the surface; capsule length 12.4–14.2 mm, diameter 7.3–9.1 mm; capsule contents — homogeneous dark yellow suspension.

Pharmacotherapeutic group. Systemic anti-acne agents.

ATC code: D10BA01.

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, it has been established that clinical improvement in severe acne is associated with reduced sebaceous gland activity and histologically confirmed reduction in gland size. In addition, isotretinoin has demonstrated anti-inflammatory effects on the skin.

Efficacy

Hyperkeratosis of follicular and sebaceous gland epithelial cells leads to desquamation of corneocytes into the gland duct and subsequent obstruction by keratin and excess sebum. This results in comedone formation and, in some cases, secondary inflammatory processes. Roaccutane**®** 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 follicular duct.

Pharmacokinetics.

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 from dog studies suggests very low and variable systemic bioavailability. Administration with food increases isotretinoin bioavailability by approximately two-fold 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 lack of an intravenous formulation. Epidermal concentrations of isotretinoin 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 assays. 4-Oxo-isotretinoin, as shown in several clinical studies, contributes significantly to the therapeutic activity of isotretinoin (suppression of sebum excretion), independently of plasma levels of isotretinoin and tretinoin. The primary metabolite is 4-oxo-isotretinoin, whose steady-state plasma concentrations are 2.5 times higher than those of the parent compound. 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 metabolism via isomerization.

Enterohepatic recirculation 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, no single isoenzyme plays a dominant role. Roaccutane**®** 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 is longer, averaging 29 hours.

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

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 and 4-oxo-isotretinoin.

Clinical characteristics.

Indications.

Severe forms of acne (including nodular and conglobate acne, acne with tendency to permanent scarring) unresponsive to standard treatment (systemic antibacterial therapy, topical treatment).

Before initiating isotretinoin treatment, two independent physicians prescribing the drug must agree that no other appropriate effective treatment is available (see section "Children").

Contraindications.

Pregnancy and breastfeeding. Should not be used in women of childbearing potential unless all requirements of the "Pregnancy Prevention Program" are met. Hypersensitivity to isotretinoin or to any component of the drug; hepatic impairment; severe hyperlipidemia; hypervitaminosis A; concomitant therapy with tetracyclines. Since Roaccutane**®** contains refined soybean oil, partially hydrogenated soybean oil, and hydrogenated soybean oil, the drug is contraindicated in patients with peanut or soy allergy.

Interaction with other medicinal products and other forms of interaction.

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

Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of isotretinoin and tetracyclines. Therefore, concomitant use with tetracyclines is contraindicated (see sections "Contraindications", "Special precautions for use").

Concomitant use with topical keratolytic or exfoliative agents for acne treatment should be avoided due to possible increased local irritation (see section "Special precautions for use").

Special precautions for use.

Teratogenic effects

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

Roaccutane**®** is absolutely contraindicated:

• in pregnant women;
• in women of childbearing potential if all conditions of the "Pregnancy Prevention Programme" are not met.

Pregnancy Prevention Programme

This medicinal product is TERATOGENIC.

Roaccutane**®** is contraindicated in women of childbearing potential, except in cases where all the following conditions are met:

• the woman has been diagnosed with severe acne (nodular and conglobate acne, acne prone to permanent scarring) that is unresponsive to standard treatment (systemic antibiotic therapy, topical treatment) (see section "Indications");
• 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 visits to the physician;
• the woman understands and agrees to the necessity of using effective contraception continuously for one month before starting treatment, throughout the entire treatment period, and for one month after treatment ends. At least one highly effective method of contraception (whose efficacy does not depend on user compliance) or two complementary methods of contraception (whose efficacy depends on user compliance) should be used;
• in each individual case, the choice of contraceptive method takes into account individual circumstances, and the patient is involved in the discussion of contraceptive choice to obtain her approval and agreement to adhere to the rules of use of the selected methods;
• even in the case of amenorrhea, the woman uses reliable contraceptive methods;
• the woman has been informed about the danger of becoming pregnant during treatment with Roaccutane**®** and understands the necessity of immediate consultation in case of suspected or confirmed pregnancy;
• the woman understands the necessity and agrees to regularly perform pregnancy testing before treatment, ideally monthly during treatment, and one month after treatment completion;
• the woman confirms that she is aware of the risks associated with isotretinoin use and the need to take preventive measures.

These conditions also apply to sexually inactive women, except when the physician is certain that there is no risk of pregnancy.

The physician must be confident that:

• the patient is capable of fulfilling all the above-mentioned conditions for pregnancy prevention and has an adequate level of understanding;
• the patient has been informed of the above conditions;
• the patient understands the necessity of continuous and correct use of at least one highly effective method of contraception (i.e., a method whose efficacy does not depend on user compliance) or two complementary methods of contraception (whose efficacy depends on user compliance), starting at least one month before treatment initiation, continuing throughout the entire treatment period, and for at least one month after treatment cessation;
• a negative result of a reliable pregnancy test has been obtained before starting the drug, during treatment, and one month after therapy completion. The date and results of the pregnancy test must be documented.

If pregnancy occurs in a woman receiving isotretinoin, treatment with the drug should be discontinued immediately, and the patient should be referred to a physician specialized in or experienced in teratology for evaluation and recommendations.

If pregnancy occurs after completion of treatment, there remains a risk of severe and serious fetal malformations. This risk persists until the drug is completely eliminated from the body, which takes approximately one month after treatment ends.

Pregnancy prevention.

Patients should be informed about contraceptive methods. If they are not using contraception, the physician should provide necessary 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 childbearing potential must use at least one highly effective method of contraception (whose efficacy does not depend on user compliance) or two complementary methods of contraception (whose efficacy depends on user compliance). Contraceptive methods should be used for at least one month before starting treatment, throughout the entire treatment period, and for at least one month after discontinuation of Roaccutane**®**, even in patients with amenorrhea.

When selecting a contraceptive method in each individual case, individual circumstances should be evaluated, and the patient should be involved in the discussion of contraceptive choice to obtain her approval and agreement to adhere to the rules of use of the selected methods.

Pregnancy testing.

According to current practice, a pregnancy test with a minimum sensitivity of 25 mIU/mL is recommended, performed under medical supervision, as specified below.

Before starting treatment

At least one month after starting contraception and shortly before (ideally a few days before) the first prescription of the drug, the patient should undergo a pregnancy test under medical supervision to confirm she is not pregnant at the start of isotretinoin treatment.

During treatment

The patient should visit the physician regularly, ideally monthly. The need for monthly pregnancy testing under medical supervision is determined according to local practice, taking into account the patient's sexual activity, recent menstrual history (abnormal menstruation, lack of regularity, or amenorrhea), and contraceptive method. If indicated, the pregnancy test should be performed on the day of the scheduled visit or up to three days before the visit.

End of treatment

A final pregnancy test should be performed one month after treatment completion.

Prescription of the medicinal product Roaccutane**®** to women of childbearing potential should ideally be limited to 30 days to ensure regular monitoring, including pregnancy testing. Pregnancy testing, prescription issuance, and drug dispensing are recommended to be performed on the same day. Dispensing of Roaccutane**®** at the pharmacy should occur no later than 7 days after prescription issuance.

This monthly monitoring ensures regular pregnancy testing and monitoring, and confirms that the patient is not pregnant before prescribing the next course of treatment.

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

Male patients.

Available data indicate that exposure of the drug via semen and seminal fluid from men taking Roaccutane**®** is insufficient to cause teratogenic effects in women.

Male patients should be reminded not to give the drug to others, especially women.

Additional warnings

Microdoses of progesterone-only contraceptives may be inadequate for contraception during treatment with Roaccutane**®**.

Patients must never give this medicinal product to others and should return any unused capsules to the physician after treatment completion.

Patients must not donate blood during treatment and for one month after its cessation, due to the risk of transfusion transmission to a fetus of a pregnant woman.

Psychiatric disorders

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

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

Before starting isotretinoin treatment, all patients should undergo a psychiatric health assessment and be regularly monitored during treatment for the development or worsening of psychiatric disorders. Particular caution is required in patients with a history of depression. If necessary, appropriate treatment for psychiatric disorders should be initiated. Discontinuation of Roaccutane**®** may not resolve psychiatric symptoms—further specialist monitoring may be required.

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

Sexual dysfunction

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

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

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

Educational materials

To assist physicians, pharmacists, and patients in avoiding the risk of isotretinoin exposure to the fetus, the marketing authorization holder provides educational materials with warnings regarding the teratogenic effects of isotretinoin, as well as recommendations on contraception use before starting therapy and the necessity of pregnancy testing.

Physicians must provide full information about the teratogenic risk and strict measures to prevent pregnancy according to the "Pregnancy Prevention Programme" to all patients, both men and women of reproductive potential (every woman who could become pregnant).

Additionally, educational materials include warnings about other risks associated with isotretinoin use, particularly regarding mental health and sexual function.

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.

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

Deep chemical peels and laser treatments should not be performed during Roaccutane**®** treatment or within 5–6 months after treatment, due to the high risk of hypertrophic scarring in atypical areas and, less frequently, hyper- and hypopigmentation in treated areas. Waxing for hair removal should not be performed during Roaccutane**®** treatment or within 6 months after treatment due to the risk of epidermal detachment.

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

Patients receiving Roaccutane**®** 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.

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

Allergic reactions

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

Ocular disorders

Dry eyes, corneal opacities, night vision impairment, and keratitis usually resolve after discontinuation of the drug. Cases of persistent dry eyes after therapy cessation have been reported. Moisturizing eye ointments or artificial tears may be used for dryness of the ocular mucosa. In case of intolerance to contact lenses, glasses should be used during treatment.

In some patients, twilight vision acuity may decrease, sometimes suddenly (see section "Ability to affect reaction speed when driving or operating machinery"). Patients with visual complaints should be referred to an ophthalmologist, and discontinuation of the drug should be considered.

Musculoskeletal and connective tissue disorders

Patients receiving isotretinoin may experience muscle and joint pain, and serum creatine phosphokinase levels may increase, especially with intense physical exertion (see section "Adverse reactions"). In some cases, this may progress to potentially life-threatening rhabdomyolysis.

After several years of Roaccutane**®** use for keratinization disorders at very high doses, bone changes have been observed, including premature closure of epiphyseal growth plates, hyperostosis, ligament and tendon calcification. Doses, treatment duration, and total cumulative doses in these patients generally exceeded those recommended for acne treatment.

Cases of sacroiliitis have been reported in patients receiving isotretinoin. To differentiate sacroiliitis from other causes of back pain, patients with clinical signs of sacroiliitis may require additional investigations, including imaging methods such as MRI. In post-marketing reports, sacroiliitis regressed after discontinuation of the drug and 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, one month after initiation, and then every three months, unless clinical indications require more frequent monitoring. Transient and reversible increases in liver transaminase levels have been observed, mostly within normal limits, returning to baseline during treatment. If transaminase levels exceed normal values, the dose should be reduced or the drug discontinued.

Renal impairment

Renal function impairment or renal insufficiency does not affect the pharmacokinetics of isotretinoin. Therefore, isotretinoin may be used in patients with renal insufficiency. 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, one month after initiation, then every three 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. Triglyceride levels exceeding 800 mg/dL (or 9 mmol/L) may lead to acute pancreatitis, possibly with fatal outcome.

Gastrointestinal disorders

Inflammatory bowel disease (including regional ileitis) may develop during isotretinoin treatment. The drug should be discontinued immediately in patients with severe (hemorrhagic) diarrhea.

High-risk groups

Patients with diabetes mellitus, 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 levels and new-onset diabetes mellitus have been reported during isotretinoin therapy.

Excipients

This medicinal product contains 2–3.05 mg of sorbitol (E 420) in each 10 mg capsule.

This medicinal product contains 3.2–4.86 mg of sorbitol (E 420) in each 20 mg capsule.

The additive effect of concomitantly administered medicinal products containing sorbitol (or fructose), as well as dietary intake of sorbitol (or lactose), should be considered.

The sorbitol content in oral medicinal products may affect the bioavailability of other orally administered medicinal products when used concomitantly.

Use during pregnancy or breastfeeding.

Pregnancy

Pregnancy is an absolute contraindication for the use of the medicinal product Roaccutane ® (see section "Contraindications"). Women of childbearing potential must use effective contraception during treatment and for one month after treatment. If pregnancy occurs despite preventive measures during the period when the woman is taking Roaccutane ®, or within one month after therapy completion, there is a very high risk of severe and serious fetal malformations.

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

If pregnancy occurs in a woman undergoing 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 consultation.

Breastfeeding.

Due to the high lipophilicity of isotretinoin, it is highly likely to be excreted in breast milk. Because of possible adverse effects in the infant due to drug exposure through breast milk, the use of Roaccutane® 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 or development.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product Roaccutane**®** may potentially affect the ability to drive or operate machinery.

During and rarely after treatment, some patients have experienced reduced twilight vision acuity (see sections "Adverse reactions", "Special precautions for use"). Since these effects may occur suddenly in some individuals, patients should be informed of this possibility and advised to exercise caution when driving or operating machinery.

Very rare 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 activities 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.

Capsules should be taken during meals, 1–2 times daily.

Adults (including adolescents and elderly patients). Treatment should be initiated at a dose of 0.5 mg/kg per day. The therapeutic response to isotretinoin and some adverse reactions are dose-dependent and vary among individual patients. Therefore, individual dose adjustment is necessary during treatment. In most patients, the dose ranges from 0.5 to 1 mg/kg body weight per day.

Long-term remission and recurrence rate are more closely related to the cumulative dose than to the duration of treatment or daily dose. It has been established that no additional benefit is expected from using a cumulative dose exceeding 120–150 mg/kg. The duration of therapy depends on the daily dose. A treatment course of 16–24 weeks is usually sufficient to achieve remission.

In most patients, acne completely resolves after a single course of treatment. In case of significant recurrence, a repeat course of Roaccutane**®** treatment should be administered at the same daily and cumulative dose as the first course. Since improvement may continue for up to 8 weeks after completion of treatment, a repeat course should not be initiated earlier than at the end of this period.

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 Warnings and Precautions for Use").

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

Children.

Roaccutane**®** should not be used for the treatment of acne in the prepubertal period. The medicinal product is not recommended for children under 12 years of age due to lack of data on efficacy and safety.

Before initiating isotretinoin treatment in patients under 18 years of age, two independent physicians prescribing the medicinal product must agree that no other appropriate and effective treatment is available (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. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and pruritus. Symptoms of accidental or intentional isotretinoin 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), and eyes (conjunctivitis).

For the description of adverse reaction frequencies, the following categories are used: 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 — skin allergic reactions, anaphylactic reactions, hypersensitivity reactions.

Metabolism and nutrition disorders: very rare — diabetes mellitus, hyperuricemia.

Psychiatric disorders: uncommon — aggression, anxiety, mood changes; very rare — behavioral 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, contact lens intolerance, corneal opacity, reduced twilight vision, keratitis, optic disc swelling (as a 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 for use").

Hepatobiliary disorders: very common — increased transaminases (see section "Special precautions for use"); very rare — hepatitis.

Skin and subcutaneous tissue disorders: very common — cheilitis, dermatitis, skin dryness, localized desquamation, pruritus, erythematous rash, skin fragility (risk of injury due to friction); uncommon — alopecia; very rare — fulminant forms of acne, acne flare (acne erythema), erythema (face), exanthema, hair disorders, hirsutism, onychodystrophy, paronychia, photosensitivity, 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 dysfunction, genital hypoesthesia.

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

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

Reporting of suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children.

Store at a temperature not exceeding 25 °C in the original packaging to protect from moisture and light.

Packaging.

10 capsules of 10 mg or 20 mg in blisters made of PVC/PE/PVDC/aluminium foil or PVC/PVDC/aluminium foil. 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ketelent Germany Eberbach GmbH

Manufacturer's address.

Hammelbacher Strasse 2, Eberbach, Baden-Württemberg, 69412, Germany.