Instructions for Aknetin capsules 8 mg blister No. 30
Composition
active ingredient: isotretinoin;
1 capsule contains 8 mg of isotretinoin;
excipients: stearyl macrogolglycerides, refined soybean oil, sorbitan oleate, gelatin, titanium dioxide (E 171), red iron oxide (E 172) (for 8 mg dosage), indigo carmine (E 132) (for 16 mg dosage), yellow iron oxide (E 172) (for 16 mg dosage).
Dosage form
Capsules.
Main physicochemical properties:
8 mg capsules – gelatin capsules No. 3 with a red-brown body and cap. The contents of the capsules are a waxy orange paste.
Pharmacotherapeutic group
Means for the systemic treatment of acne. ATX 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, but it has been shown that improvement in severe acne is associated with decreased sebaceous gland activity and histologically confirmed reduction in sebaceous gland size. In addition, isotretinoin has been shown to have anti-inflammatory effects on the skin.
Efficiency
Hyperkeratosis of the epithelial cells of the hair follicle and sebaceous gland leads to the exfoliation of corneocytes into the duct of the gland and to the blockage of the latter with keratin and excess sebum. After which a comedone is formed and in some cases an inflammatory process joins. Aknetin® inhibits the proliferation of sebocytes and acts on acne, restoring the normal process of cell differentiation. Sebum is the main substrate for the growth of Propinibacterium acnes, a decrease in sebum production inhibits bacterial colonization of the duct.
Pharmacokinetics
Absorption
The absorption of isotretinoin from the gastrointestinal tract is variable and linearly dependent on the dose of the drug in the therapeutic dosage range. The absolute bioavailability of isotretinoin has not been determined, since there is no dosage form for intravenous administration, but extrapolation of the results of a study in dogs suggests a very low and variable systemic bioavailability. Taking isotretinoin with food increases its bioavailability by twofold compared with taking it on an empty stomach.
Distribution
Isotretinoin is almost completely bound to plasma proteins (99.9%), mainly albumin. The volume of distribution of isotretinoin in humans is unknown, as there is no intravenous formulation. Epidermal concentrations of isotretinoin are only half those in serum. Plasma concentrations of isotretinoin are approximately 1.7 times higher than whole blood concentrations due to poor penetration of isotretinoin into erythrocytes.
Metabolism
After oral administration, three major metabolites are observed in plasma: 4-oxo-isotretinoin, tretinoin (all-trans-retinoic acid), and 4-oxo-retinoin. These metabolites have demonstrated biological activity in several in vitro tests. 4-oxo-isotretinoin has been shown in several clinical studies to contribute significantly to the therapeutic activity of isotretinoin (sebum suppression, independent of plasma levels of isotretinoin and tretinoin). The major metabolite is 4-oxo-isotretinoin, with steady-state plasma concentrations 2.5-fold higher than those of the parent drug. Other metabolites, including glucuronide conjugates, are minor.
Since isotretinoin and tretinoin (all-trans-retinoic acid) are interconvertible, the metabolism of tretinoin is linked to that of isotretinoin. It has been estimated that 20-30% of an isotretinoin dose is metabolized by isomerization.
Enterohepatic circulation may play a significant role in the pharmacokinetics of isotretinoin in humans.
In vitro metabolism studies have shown that several CYP enzymes are involved in the conversion of isotretinoin to 4-oxo-isotretinoin and tretinoin. No one isoform appears to play a dominant role. Aknetin® and its metabolites have no significant effect on the activity of CYP enzymes.
Breeding
After oral administration of radiolabeled isotretinoin, approximately equal amounts of isotretinoin are recovered in urine and feces. The terminal elimination half-life of the unchanged drug after oral administration to acne patients averages 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin ranges from 7 to 39 hours.
Isotretinoin belongs to the natural (physiological) retinoids. Endogenous concentrations
Retinoids are restored approximately 2 weeks after stopping the use of Aknetin®.
Pharmacokinetics in special clinical cases
Since isotretinoin is contraindicated in patients with impaired liver function, data on the pharmacokinetics of the drug in this group of patients are limited.
Renal failure does not significantly reduce the plasma clearance of isotretinoin or 4-oxo-isotretinoin.
Indication
Severe forms of acne (including nodular and conglobatic acne, acne with a tendency to permanent scarring) that are not amenable to standard treatment methods (systemic antibacterial therapy, topical treatment).
Contraindication
Pregnancy and breastfeeding; in women of reproductive age if all conditions of the "Pregnancy Prevention Program" are not met; hypersensitivity to isotretinoin or to any components of the drug; liver failure; severe hyperlipidemia; hypervitaminosis A; concomitant therapy with tetracyclines. Due to the fact that Aknetin® contains soybean oil, the drug is contraindicated for use in patients with allergies to peanuts and soybeans.
Interaction with other medicinal products and other types of interactions
Due to possible exacerbation of symptoms of hypervitaminosis A, simultaneous administration of Aknetin® and vitamin A should be avoided.
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of isotretinoin with tetracyclines. Therefore, concomitant use with tetracyclines should be avoided (see sections 4.3 and 4.4).
Combined use with topical keratolytic or exfoliative drugs for the treatment of acne is contraindicated due to possible increased local irritation (see section "Special instructions").
Application features
Teratogenic effects
The drug Aknetin® is a strong teratogen for humans and induces a high incidence of severe and life-threatening congenital malformations.
The drug Aknetin® is clearly contraindicated: for pregnant women, women of reproductive age if all conditions of the "Pregnancy Prevention Program" are not met (see below).
"Pregnancy Prevention Program"
This drug is TERATOGENIC
Aknetin® is contraindicated in women of reproductive age unless all of the following conditions are met:
a woman has been diagnosed with a severe form of acne (nodular and conglobatic acne, acne with a tendency to permanent scarring), which is not amenable to standard treatment methods (systemic antibacterial therapy, local treatment); (see the section "Contraindications")
the potential for pregnancy should be assessed in all women; the woman understands the teratogenic risk of the drug; the woman understands the need for a mandatory monthly visit to the doctor; the woman understands and agrees to the need to use effective contraception, continuously, for 1 month before starting treatment with Aknetin®, during treatment and for a month after the end of treatment. At least one highly effective method of contraception (i.e. one that is not dependent on the user) or two complementary methods of contraception that are dependent on the user should be used simultaneously for at least 1 month before starting treatment with Aknetin®, during treatment and for a month after the end of treatment; when choosing a contraceptive method in each specific case, the individual circumstances should be assessed and the patient should be invited to a discussion, in order to guarantee her involvement and compliance with the use of the chosen methods. even in the event of amenorrhea, the woman should adhere to reliable contraceptive methods; the woman should confirm that she understands the essence of the precautions; the woman is informed about the risk of pregnancy during treatment with Aknetin® and understands the need to seek immediate advice if pregnancy is suspected or if pregnancy occurs; the woman understands the need and agrees to regularly perform a pregnancy test before, during and 5 weeks after treatment; the woman confirms that she is aware of the risks of isotretinoin use and the need for precautions.
The use of contraceptives according to the above recommendations during treatment with isotretinoin should be recommended even to sexually inactive women, unless the doctor believes that there are all grounds to suggest that there is no risk of pregnancy.
The doctor must be sure that:
the patient is able to understand and comply with all of the above-mentioned pregnancy prevention requirements; the patient is familiar with the above-mentioned conditions; the patient is aware of the need to consistently and correctly use at least one highly effective method of contraception (i.e. a method that is not dependent on the user) or two complementary methods of contraception that are dependent on the user at the same time; the patient confirms that she is familiar with the above-mentioned conditions; a negative result of a reliable pregnancy test was obtained before starting the drug, during treatment and 1 month after the end of therapy. The dates and results of the pregnancy test should be documented. If pregnancy occurs in a woman receiving isotretinoin treatment, treatment should be discontinued and the patient should be referred to a physician who specializes in or has experience in teratology for examination and advice. If pregnancy occurs after the end of treatment, there is a risk of severe and serious birth defects in the fetus. This risk persists until the drug is completely eliminated from the body, which occurs within one month after the end of treatment.
Pregnancy prevention.
As a minimum, women of reproductive age should use at least one highly effective method of contraception (i.e., one that is not dependent on the user) or two complementary methods of contraception that are dependent on the user at the same time. Contraceptive methods should be used for at least 1 month before starting treatment with Aknetin®, during treatment and for a month after the end of treatment, even in patients with amenorrhea. When choosing a contraceptive method in each case, the individual circumstances should be assessed and the patient should be invited to a discussion in order to ensure her involvement and compliance with the chosen methods.
Pregnancy test
According to current practice, it is recommended to perform a pregnancy test with a minimum sensitivity of 25 mIU/ml under medical supervision in the first 3 days of the menstrual cycle.
Before starting treatment
At least one month after the patient has started using contraception and shortly (preferably a few days) before the first dose, the patient should undergo a pregnancy test under medical supervision to ensure that the patient is not pregnant at the time of starting isotretinoin treatment. The results of the test should be recorded by the specialist.
In patients with irregular menstrual cycles, the timing of pregnancy testing depends on sexual activity. The test should be performed 3 weeks after unprotected intercourse. The physician should inform the patient about contraceptive methods.
The drug can only be prescribed to patients who have been using effective contraception for at least 1 month before starting treatment with Aknetin®. A test should ensure that the patient is not pregnant at the time of starting treatment with isotretinoin.
During treatment
The patient should visit the doctor at regular intervals, ideally once a month. The need for monthly pregnancy testing is determined according to local practice and taking into account sexual activity and recent menstrual history (abnormal menstruation, irregularity or amenorrhea). If indicated, a pregnancy test should be performed on the day of the visit or 3 days before the visit.
Completion of treatment
A final pregnancy test is performed 1 month after the end of treatment.
Precautions regarding the prescription and distribution of the drug.
Ideally, women of reproductive age should only be prescribed Aknetin® for 30 days of treatment; continued treatment requires a new prescription from a doctor.
Ideally, pregnancy testing, prescription, and medication
is recommended to be carried out within one day. The dispensing of Aknetin® in the pharmacy should only be carried out within a maximum of 7 days from the date of prescription. Such monthly monitoring will allow for regular pregnancy testing and to ensure that the patient is not pregnant before receiving the next course of the drug.
Male patients
Existing evidence suggests that in women, exposure to the drug from semen and
fluid of men who used Aknetin® is insufficient to cause teratogenic effects
Aknetin®. Men should exclude the possibility of the drug being used by other people, especially women.
Additional warnings
Patients should be informed never to give this medicine to other people and to return any unused capsules to their doctor after completing treatment.
Patients should not donate blood during treatment and for 1 month after its discontinuation, as there is a potential risk of transfusion transmission to the fetus of a pregnant woman.
Educational materials
To help doctors, pharmacists and patients avoid the risk of Aknetin® exposure to
fetus, the manufacturing company provides educational materials aimed at preventing the teratogenic effects of the drug, recommendations on the use of contraception before starting therapy, and recommendations on the need for pregnancy testing.
Complete information about teratogenic risk and strict adherence to pregnancy prevention measures is contained in the Pregnancy Prevention Program, which must be provided to all patients – both men and women.
Mental disorders
Depression, aggravated depression, anxiety, aggressive tendencies, mood swings, psychotic symptoms and very rarely suicidal thoughts, suicide attempts and suicide have been reported in patients treated with Aknetin® (see section "Adverse reactions"). Caution should be exercised in patients with a history of depression and patients should be monitored for the development of depression during treatment, and patients should be referred to appropriate specialists if necessary. However, withdrawal of Aknetin® may not lead to resolution of symptoms and further specialist monitoring may be required. Awareness of family or friends may be useful in identifying mental health disorders.
Skin and subcutaneous tissue disorders
In rare cases, at the beginning of therapy, an exacerbation of acne is observed, which usually resolves after 7-10 days without adjusting the dose of the drug.
Avoid excessive exposure to sunlight or UV rays. If sun protection is necessary, use a high protection factor (SPF) with at least 15.
Aknetin® and for 5-6 months after treatment, as there is a high risk of hypertrophic scars in atypical areas and, less commonly, hyper- and hypopigmentation in the treatment 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 exfoliative agents for the treatment of acne should be avoided due to the possibility of increased local irritation (see section “Interaction with other medicinal products and other types of interactions”).
Patients receiving Aknetin® are recommended to use moisturizing ointments or body creams, lip balm to reduce dryness of the skin and lips at the beginning of treatment.
In the post-marketing period, cases of severe skin reactions (erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported. Since these cases may be difficult to distinguish from other skin reactions that may occur (see section 4.8), patients should be warned about the signs and symptoms of these diseases and be closely monitored for severe skin reactions. If severe skin reactions are suspected, isotretinoin treatment should be discontinued.
Allergic reactions
Anaphylactic reactions have been reported rarely, in some cases following previous topical retinoid use. Allergic skin reactions have been reported uncommonly.
Serious cases of allergic vasculitis, often with purpura (bruises and red spots), as well as non-cutaneous manifestations, have been reported. Serious allergic reactions require discontinuation of therapy and careful monitoring of the patient.
Vision disorders
Dry eyes, corneal clouding, night vision impairment, and keratitis usually resolve
after discontinuation of the drug. In case of dryness of the mucous membrane of the eye, you can use moisturizing eye ointment or artificial tear preparations. In case of intolerance to contact lenses, glasses should be used during treatment.
Some patients may experience a decrease in night vision acuity, sometimes occurring suddenly (see
(see section “Ability to influence the reaction speed when driving vehicles or operating other mechanisms”). If there are complaints about vision, such patients should be referred to an ophthalmologist and the issue of drug withdrawal should be considered.
Musculoskeletal and connective tissue disorders
When using Aknetin®, muscle and joint pain and increased serum creatine phosphokinase may occur, especially during intense physical exertion (see section "Adverse reactions"). In some cases, this may progress to rhabdomyolysis, which is a life-threatening condition for the patient.
Several years after the use of isotretinoin for the treatment of dyskeratosis at very high doses, bone changes have developed, requiring more frequent monitoring. Transient and reversible elevations of hepatic transaminases have been reported, in most cases within normal limits, which returned to normal during treatment. If transaminase levels exceed normal limits, the dose of the drug should be reduced or discontinued.
Benign intracranial hypertension
Cases of benign intracranial hypertension have been described, some of which were caused by concomitant use with tetracyclines (see sections "Contraindications", "Interaction with other medicinal products and other types of interactions"). Symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and swelling of the optic nerve head. Patients who develop benign intracranial hypertension should immediately discontinue the drug.
Hepatobiliary disorders
It is recommended to monitor liver enzymes before treatment, 1 month after its initiation, and then every 3 months, unless there is a clinical indication for more frequent monitoring. Transient and reversible increases in liver transaminase levels have been observed, in most cases within normal limits, which returned to baseline during treatment. If transaminase levels exceed the normal range, the dose of the drug should be reduced or discontinued.
Kidney failure
Renal impairment or renal failure does not affect pharmacokinetics.
isotretinoin. Therefore, isotretinoin can be taken by patients with renal insufficiency.
However, it is recommended to start with a low dose and titrate it to the maximum tolerated dose (see section "Method of administration and dosage").
Lipid metabolism
Fasting serum lipid levels should be measured (prior to treatment, 1 month after initiation, then every 3 months unless clinically indicated for more frequent monitoring). Elevated serum lipids usually resolve after dose reduction or discontinuation and with diet. Isotretinoin has been associated with increases in triglycerides. Isotretinoin should be discontinued in the event of uncontrolled hyperlipidemia or symptoms of pancreatitis.
An increase in triglyceride levels above 800 mg/dL or 9 mmol/L may be accompanied by
development of acute pancreatitis, possibly fatal.
Inflammatory bowel disease (including regional ileitis) may develop in patients without pre-existing bowel disease during treatment with isotretinoin. Patients with severe (hemorrhagic) diarrhea should immediately discontinue the drug.
High-risk groups
Patients with diabetes mellitus, obesity, alcoholism or lipid metabolism disorders may require more frequent monitoring of serum glucose and/or lipids during treatment with isotretinoin. Increased fasting blood sugar and new cases of diabetes mellitus have been reported during treatment with isotretinoin.
Fructose intolerance
The medicinal product contains sorbitan oleate. Patients with hereditary fructose intolerance should not take this medicinal product.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug has the potential to affect the ability to drive and use machines. During treatment and in rare cases after treatment, some patients have experienced a decrease in twilight vision (see sections "Adverse reactions", "Special instructions"). Since in some individuals the manifestation of these phenomena was sudden, patients should be informed of the possibility of this problem and warned about the need to be careful when driving or operating other mechanisms. Very rarely, cases of drowsiness, dizziness, visual impairment have been reported. Patients should be warned that if these symptoms occur, they should not drive, operate machinery or participate in any other activity that may put themselves or others at risk.
Use during pregnancy or breastfeeding
Pregnancy
Pregnancy is an absolute contraindication to the use of Aknetin® (see section "Contraindications"). Women of childbearing potential should use effective contraception during treatment and for one month after treatment. If pregnancy occurs while a woman is taking Aknetin®, despite precautions, or within one month after the end of therapy, there is a very high risk of giving birth to a child with severe and serious developmental defects.
Fetal malformations associated with isotretinoin include central nervous system abnormalities (hydrocephalus, cerebellar malformations/abnormalities, microcephaly), facial malformations, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canal), eye malformations (microphthalmia), cardiac and vascular anomalies (conotruncal heart defects such as tetralogy of Fallot, transposition of the great vessels, septal defect), thymic and parathyroid gland abnormalities. In addition, the risk of spontaneous abortions is increased.
If pregnancy occurs in a woman receiving isotretinoin treatment, therapy should be discontinued and a physician specializing and experienced in teratology should be consulted for evaluation and advice.
Breast-feeding
Due to the high lipophilicity of isotretinoin, there is a high possibility that it will pass into breast milk. Due to possible side effects in the child associated with the action of the drug through breast milk, the use of isotretinoin is contraindicated in women during breastfeeding (see section "Contraindications").
Fertility
Isotretinoin in therapeutic doses does not affect the number, motility, or morphology of sperm and does not compromise the formation and development of the embryo in men taking isotretinoin.
Method of administration and doses
Standard dosing regimen
Isotretinoin treatment should only be prescribed and administered by a physician who is experienced in the use of systemic retinoids for the treatment of severe acne and is fully aware of the risks of retinoid therapy and the requirements for monitoring patients.
Aknetin® is prescribed to adults and children over 12 years of age, starting at a dose of 0.4 mg/kg per day. The capsules should be taken with meals 1 or 2 times a day.
If you miss a prescribed dose of the drug, it is not recommended to take a double dose of the drug!
The therapeutic response to Aknetin®, as well as the undesirable effects, are dose-dependent and have varying degrees of severity. This requires individual dose adjustment during treatment. For most patients, the dose is from 0.4 to 0.8 mg/kg per day.
Often at the beginning of treatment, a short-term exacerbation of the disease is noted. The effectiveness of treatment and side effects vary from patient to patient, so after 4 weeks of therapy, the dose should be individually adjusted for adults from 0.1 to 1 mg/kg per day. The maximum daily dose of 1 mg/kg can be prescribed only for a limited time.
Typically, the course of treatment lasts from 16 to 24 weeks. When evaluating the results of therapy, it is necessary to remember that the effect of the drug often persists after discontinuation of treatment. In this regard, a repeated course should be prescribed no earlier than after 8 weeks.
For patients who do not tolerate the recommended doses, treatment may be continued at a lower dose, which should be accompanied by an increase in the duration of treatment and may accordingly increase the risk of relapse. For such patients, treatment should be continued at the maximum tolerated dose.
Children
The drug should not be used to treat acne in the prepubertal period and the drug is not recommended for children under 12 years of age, as safety and efficacy in this age group have not been studied.
Overdose
Isotretinoin is a derivative of vitamin A. Although the acute toxicity of isotretinoin is low, signs of hypervitaminosis A may occur in the event of accidental overdose. Manifestations of acute vitamin A toxicity include severe headache, nausea or vomiting, drowsiness, irritability, and itching. Symptoms of accidental and intentional overdose are likely to be the same. These symptoms are reversible and resolve without the need for treatment.
Adverse reactions
Some side effects of isotretinoin are dose-related. Adverse reactions are usually reversible after dose adjustment or discontinuation of the drug, but some may persist after discontinuation of treatment. The most commonly reported symptoms with isotretinoin are dryness of the skin, mucous membranes, including the lips (cheilitis), nose (epistaxis), and eyes (conjunctivitis).
The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), rare (≥1/10,000, <1/1,000), very rare (≤1/10,000), frequency unknown (frequency cannot be estimated from the available data).
Infections: very rarely common – gram-positive bacterial infections of the skin and mucous membranes.
From the blood and lymphatic system: very common - anemia, increased ESR, thrombocytopenia, thrombocytosis; common - neutropenia; very rare - lymphadenopathy.
On the part of the immune system: rarely - allergic skin reactions, anaphylactic reactions, hypersensitivity reactions.
From the side of metabolism: very rarely - diabetes mellitus, hyperuricemia.
Psychiatric disorders: rare – depression, increased depression, tendency to aggression, anxiety, mood changes; very rare – conduct disorder, psychotic disorders, suicidal thoughts, suicide attempts, suicide.
Nervous system disorders: common - headache; very rare - benign intracranial hypertension, convulsions, drowsiness, dizziness.
From the organs of vision: very common - blepharitis, conjunctivitis, dry eyes,
eye irritation; very rarely common – blurred vision, cataract, color vision impairment, contact lens intolerance, corneal opacity, decreased twilight vision, keratitis, optic nerve head swelling (as a manifestation of benign intracranial hypertension), photophobia, visual impairment.
From the side of the organs of hearing and labyrinth: very rarely - hearing impairment.
Vascular disorders: very rare - vasculitis (e.g. Wegener's granulomatosis, allergic vasculitis).
Respiratory, thoracic and mediastinal disorders: common - epistaxis, dry nose, nasopharyngitis; very rare - bronchospasm (especially in patients with asthma), dysphonia.
Gastrointestinal tract: very rarely - colitis, ileitis, dry throat, gastrointestinal bleeding, hemorrhagic diarrhea, inflammatory bowel disease, nausea, pancreatitis (see section "Special instructions").
Hepatobiliary system: very common - increased transaminases (see section "Special instructions for use"); very rare - hepatitis.
Skin and subcutaneous tissue disorders: very common - cheilitis, dermatitis, dry skin, localized peeling, itching, erythematous rash, skin trauma (risk of injury from friction); rare - alopecia; very rare - acne fulminant, acne exacerbation (acne hyperemia), erythema (face), exanthema, hair disorders, hirsutism, onychodystrophy, paronychia, photosensitivity, pyogenic granuloma, skin hyperpigmentation, increased sweating; frequency unknown* - 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 unknown* – rhabdomyolysis.
On the part of the kidneys and urinary system: very rarely - glomerulonephritis.
Reproductive system and breast disorders: frequency unknown* – sexual dysfunction, including erectile dysfunction and decreased libido, gynecomastia.
General disorders: very rarely common – granulation tissue (increased formation), increased fatigue.
Laboratory parameters: very common - hypertriglyceridemia, decreased high-density lipoprotein levels; common - hypercholesterolemia, hyperglycemia, hematuria, proteinuria; very rare - increased CK in the blood.
*- frequency cannot be estimated based on available data.
Expiration date
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.
Vacation category
According to the recipe.
Producer
S.M.B. Technologies SA.
Location of the manufacturer and its business address
Industrial Zone - Rue du Parc Industrial 39, Marche-en-Famenne, 6900, Belgium.
