Beloretin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Beloretin (Beloretin)

Composition:

Active substance: isotretinoin;

1 capsule contains 10 mg or 20 mg of isotretinoin;

Excipients:

Capsule contents: refined soybean oil, all-rac-ɑ-tocopherol (E 307), disodium edetate (dihydrate), butylhydroxyanisole (E 320), partially hydrogenated soybean oil, hydrogenated vegetable oil, yellow wax (E 901);

Capsule shell for 10 mg: gelatin; glycerol (E 422); non-crystallizing sorbitol solution (E 420); purified water; titanium dioxide (E 171); Ponceau 4R (E 124); black iron oxide (E 172);

Capsule shell for 20 mg: gelatin; glycerol (E 422); non-crystallizing sorbitol solution (E 420); purified water; titanium dioxide (E 171); Ponceau 4R (E 124); indigocarmine (E 132).

Pharmaceutical form. Soft capsules.

Main physicochemical properties:

10 mg capsules: oval soft gelatin capsules of light violet color containing a yellow-orange, opaque, viscous liquid;

20 mg capsules: oval soft gelatin capsules of burgundy color containing a yellow-orange, opaque, viscous liquid.

Pharmacotherapeutic group. Systemic anti-acne preparations.

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 forms of 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 the epithelial cells of the hair follicle and sebaceous gland 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. Beloretin suppresses sebocyte proliferation and acts on acne by restoring normal cellular differentiation. Sebum is the primary substrate for the growth of Propionibacterium acnes; therefore, reduced sebum production inhibits bacterial colonization of the 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 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 lack of an intravenous formulation. Epidermal concentrations of isotretinoin are about half of those in blood serum. 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 is metabolized 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. Beloretin 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 half-life of unchanged drug after oral administration in patients with acne averages 19 hours. The terminal half-life of 4-oxo-isotretinoin is longer, averaging 29 hours.

Isotretinoin belongs to natural (physiological) retinoids. Endogenous retinoid concentrations return to normal approximately 2 weeks after discontinuation of Beloretin.

Pharmacokinetics in special clinical situations

As isotretinoin is contraindicated in patients with impaired liver function, pharmacokinetic data in this patient group are limited.

Renal impairment does not significantly reduce the plasma clearance of isotretinoin and 4-oxo-isotretinoin.

Clinical characteristics.

Indications.

Severe forms of acne (particularly nodular and conglobate acne, acne prone to permanent scarring) unresponsive to standard treatment methods (systemic antibacterial therapy, topical treatment).

Contraindications.

Pregnancy or breastfeeding, failure to comply with all requirements of the "Pregnancy Prevention Program" in women of childbearing potential, hypersensitivity to isotretinoin or to any of the excipients of the medicinal product, hepatic insufficiency, severe hyperlipidemia, hypervitaminosis A, concomitant therapy with tetracyclines.

Since Beloretin 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 exacerbation of symptoms of hypervitaminosis A, simultaneous administration of Beloretin 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 warnings and precautions for use").

Combined use with topical keratolytic or exfoliative agents for acne treatment should be avoided due to the potential for increased local irritation (see section "Special warnings and precautions for use").

Special precautions for use.

Teratogenic effects

Beloretin is a potent human teratogen and induces a high frequency of severe and life-threatening congenital malformations.

Beloretin is absolutely contraindicated in:

• pregnant women,
• women of childbearing potential who do not comply with all requirements of the "Pregnancy Prevention Program."

Pregnancy Prevention Program

This medicinal product is TERATOGENIC.

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

• the patient has been diagnosed with severe acne (nodular and conglobate acne, acne prone to permanent scarring) that is unresponsive to standard treatments (systemic antibacterial therapy, topical treatment) (see section "Indications");
• the potential for pregnancy must be assessed in all women;
• 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 treatment, throughout the entire treatment period, and for 1 month after treatment ends. At least one highly effective method of contraception (i.e., one that does not depend on user compliance) or two complementary user-dependent methods should be used;
• 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 ensure her adherence and agreement to follow the rules of use of the selected methods;
• even in the absence of menstruation (amenorrhea), the woman must use reliable contraceptive methods;
• the woman has been informed about the danger of becoming pregnant during treatment with Beloretin and understands the need for immediate consultation if pregnancy is suspected or confirmed;
• the woman understands and agrees to undergo regular pregnancy testing before treatment, ideally monthly during treatment, and 1 month after treatment completion;
• the woman confirms that she is aware of the risks associated with isotretinoin use and the necessity of preventive measures.

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

The physician must be confident that:

• the patient is capable of understanding and complying with all the above-mentioned conditions for pregnancy prevention and has an adequate level of understanding;
• the patient confirms that she has been informed of the above conditions;
• the patient understands the necessity and agrees to continuously and correctly use one highly effective method of contraception (i.e., one independent of user compliance) or two complementary user-dependent methods, for at least 1 month before starting treatment, throughout the entire treatment period, and for at least 1 month after discontinuation of treatment;
• a negative result from a reliable pregnancy test has been obtained before starting treatment, during treatment, and 1 month after therapy completion. The dates and results of pregnancy testing must be documented.

If pregnancy occurs in a woman receiving isotretinoin, treatment with the drug must 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 congenital malformations. This risk persists until the drug is completely eliminated from the body, which takes approximately 1 month after treatment ends.

Pregnancy prevention

Patients must be informed about contraceptive methods. If they are not using contraception, the physician must 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 childbearing potential must use at least one highly effective method of contraception (i.e., one independent of user compliance) or two complementary user-dependent methods. Contraceptive methods must be used for at least 1 month before starting treatment, throughout the entire treatment period, and for at least 1 month after discontinuation of Beloretin, 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 ensure her adherence and agreement to follow the rules of use of the selected methods.

Pregnancy testing

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

Before starting treatment

At least 1 month after the patient has started using contraception and shortly (preferably within a few days) before the first prescription of the drug, the patient should undergo a pregnancy test under medical supervision to confirm that she is not pregnant at the start of isotretinoin therapy.

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, considering the patient’s sexual activity, recent menstrual history (irregular 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 3 days before the physician visit.

End of treatment

A final pregnancy test should be performed 1 month after completion of treatment.

For women of childbearing potential, the duration of Beloretin prescription should ideally be limited to 30 days to ensure regular monitoring, including pregnancy testing. Pregnancy testing, prescription issuance, and drug dispensing are recommended to occur on the same day. Dispensing of Beloretin 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 receiving the next course of treatment.

Male patients

Available data indicate that exposure of the fetus to isotretinoin via semen and seminal fluid from men taking Beloretin is insufficient to cause teratogenic effects.

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

Additional warnings

Low-dose progestin-only contraceptives may be inadequate for contraception during treatment with Beloretin.

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

Patients must not donate blood during treatment and for 1 month after discontinuation due to the risk of transfusion-related transmission to a fetus in a pregnant woman.

Educational materials

To assist physicians, pharmacists, and patients in avoiding the teratogenic effects of Beloretin, the manufacturer provides educational materials focused on preventing teratogenic effects, recommendations for contraception use before starting therapy, and the necessity of pregnancy testing.

Complete information on teratogenic risk and pregnancy prevention measures, including the "Pregnancy Prevention Program," must be provided to all patients, both male and female.

Psychiatric disorders

Depression, depression with aggravation, anxiety, aggressive tendencies, mood changes, psychotic symptoms, and very rarely suicidal ideation, suicide attempts, and suicide have been reported in patients receiving Beloretin (see section "Adverse reactions"). Caution is required in patients with a history of depression, and patients should be monitored for the development of depression during treatment. If necessary, patients should be referred to appropriate specialists. However, discontinuation of Beloretin may not resolve psychiatric symptoms, and further specialist monitoring may be required.

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

Skin and subcutaneous tissue disorders

In isolated cases, acne may worsen at the beginning of therapy, usually resolving 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 minimum SPF of 15 should be used.

Deep chemical peels and laser treatments should not be performed during Beloretin treatment or within 5–6 months after treatment due to the high risk of hypertrophic scarring in atypical areas and, less frequently, hyper- or hypopigmentation in treated areas. Wax depilation should not be performed during treatment with Beloretin and for 6 months after treatment due to the risk of epidermal peeling.

Concomitant use of Beloretin 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 Beloretin 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 use, severe skin reactions (exudative multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Since these cases are 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 following topical use of retinoids. Allergic skin reactions have been infrequently reported. Serious cases of allergic vasculitis of the limbs, often with purpura (bruising and red spots), as well as non-cutaneous manifestations, have been reported. Serious allergic reactions require discontinuation of therapy and careful patient monitoring.

Eye disorders

Dry eyes, corneal opacities, impaired night vision, and keratitis usually resolve after discontinuation of the drug. Cases of persistent dry eyes after therapy cessation have been reported. Lubricating eye ointments or artificial tears may be used for dryness of the ocular mucosa. Contact lens intolerance may occur; glasses should be used during treatment.

Some patients may experience reduced twilight vision, which may occur suddenly (see section "Effect on ability to drive and use machines"). Patients reporting visual disturbances should be referred to an ophthalmologist, and discontinuation of the drug should be considered.

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia, and increased serum creatine phosphokinase levels have been reported in patients receiving isotretinoin, particularly with intense physical exertion (see section "Adverse reactions"). In some cases, this may progress to rhabdomyolysis, a potentially life-threatening condition.

After several years of Beloretin 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 Beloretin and appropriate treatment.

Benign intracranial hypertension

Cases of benign intracranial hypertension have been reported, some associated with concomitant use of tetracyclines (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction"). Symptoms include headache, nausea, 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 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 impairment. However, it is recommended to start with a low dose and titrate to the maximum tolerated dose (see section "Method of administration and dosage").

Lipid metabolism

Fasting serum lipid levels should be measured before treatment, 1 month after initiation, and 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. Triglyceride levels exceeding 800 mg/dL (9 mmol/L) may lead to acute pancreatitis, potentially with fatal outcomes.

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, 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 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 Beloretin (see section "Contraindications"). Women of childbearing potential must use effective contraception during treatment and for 1 month after treatment. If, despite preventive measures, pregnancy occurs while the woman is taking Beloretin , or within 1 month after therapy ends, there is a very high risk of severe and serious fetal malformations.

Fetal malformations associated with isotretinoin include central nervous system abnormalities (hydrocephalus, cerebellar hypoplasia/developmental anomalies, microcephaly), facial malformations, cleft palate, external ear anomalies (absent 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), and thymus and parathyroid gland anomalies. Additionally, the risk of spontaneous abortions is increased.

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

Breastfeeding

Due to the high lipophilicity of isotretinoin, it is highly likely to pass into breast milk. Because of potential adverse effects on the infant via breast milk, Beloretin is contraindicated in women during breastfeeding (see section "Contraindications").

Fertility

Isotretinoin at therapeutic doses does not affect sperm count, motility, or morphology and does not endanger embryo formation or development from men taking isotretinoin.

Effect on ability to drive and use machines

Beloretin may potentially affect the ability to drive and operate machinery.

During and rarely after treatment, some patients have experienced reduced twilight vision (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 rarely, 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.

Treatment with isotretinoin should 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 daily. The therapeutic response to isotretinoin and some adverse reactions are dose-dependent and may vary among individual patients. Therefore, individual dose adjustment during treatment is necessary. In most patients, the dose ranges from 0.5 to 1 mg/kg body weight daily.

Long-term remission and recurrence rates are more closely related to the total cumulative dose administered 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 cases of significant relapse, a repeat course of Beloretin 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 therapy, a repeat course should not be initiated earlier than at the end of this period.

Dosing 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), followed by gradual increase up to 1 mg/kg/day or to the maximum tolerated dose (see section "Special precautions").

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 relapse higher. To achieve maximum possible efficacy, the highest tolerated dose should be used.

Children.

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

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 itching. Symptoms of accidental or intentional isotretinoin overdose are likely to be similar. These symptoms are reversible and resolve without the need for specific 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 is stopped. The most commonly reported symptoms during isotretinoin therapy include dryness of the skin and mucous membranes, including lips (cheilitis), nasal mucosa (nasal bleeding), 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 by system organ class.

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

Blood and lymphatic system disorders: very common – anaemia, increased ESR, thrombocytopenia, thrombocytosis; common – neutropenia; very rare – lymphadenopathy.

Immune system disorders: uncommon – skin allergic reactions, anaphylactic reactions, hypersensitivity reactions.

Metabolism and nutritional disorders: very rare – diabetes mellitus, hyperuricemia.

Psychiatric disorders: uncommon – depression, worsening of depression, aggression, anxiety, mood changes; very rare – behavioral disorders, psychotic disorders, suicidal thoughts, suicide attempts, suicide.

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, decreased night 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 bleeding, haemorrhagic diarrhoea, inflammatory bowel disease, nausea, pancreatitis. Cases of severe diarrhoea have also been reported (see section "Special precautions").

Hepatobiliary disorders: very common – elevated transaminases (see section "Special precautions"); 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 hyperaemia), erythema (face), exanthema, hair disorders, hirsutism, onychodystrophy, paronychia, photosensitivity, pyogenic granuloma, skin hyperpigmentation, increased sweating; frequency not known – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

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.

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

Laboratory findings: very common – hypertriglyceridemia, decreased high-density lipoprotein levels; common – hypercholesterolemia, hyperglycemia, haematuria, proteinuria; very rare – increased blood creatine phosphokinase (CK).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 36 months.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 30 °C.

Keep out of reach and sight of children.

Packaging. 15 capsules in a blister, 2 or 4 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Belupo, pharmaceuticals and cosmetics, d.d. / Belupo, pharmaceuticals and cosmetics, Inc.

Manufacturer's address and location of operations.

Danica Street 5, 48000 Koprivnica, Croatia / Ulica Danica 5, 48000 Koprivnica, Croatia.