SUPRILEKS

INSTRUCTIONS for medical use of the medicinal product ATOMOXIN^®(ATOMOXETINE)

Composition

active substance: atomoxetine in the form of atomoxetine hydrochloride; 1 capsule contains 11.43 mg or 20.57 mg or 28.57 mg or 45.71 mg of atomoxetine hydrochloride, which is equivalent to 10 mg or 18 mg or 25 mg or 40 mg of atomoxetine; excipients: corn starch pre-gelatinized (cornstarch 1500), colloidal silicon dioxide anhydrous, dimethicone (350); capsule composition: for capsules of 10 mg: gelatin, sodium lauryl sulfate (E 487), titanium dioxide (E 171), purified water; for capsules of 18 mg: gelatin, sodium lauryl sulfate (E 487), titanium dioxide (E 171), yellow iron oxide (E 172), purified water; for capsules of 25 mg, 40 mg: gelatin, sodium lauryl sulfate (E 487), titanium dioxide (E 171), indigocarmine (E 132), purified water; printing ink (black): shellac glaze 45% (20% esterified) in ethanol, black iron oxide (E172), propylene glycol (E1520).

Pharmaceutical form

Hard capsules.

Main physical and chemical properties

Capsules of 10 mg: white powder in a hard gelatin capsule of size No. 3, opaque white cap with the inscription "10" and opaque white body with the inscription "mg"; capsules of 18 mg: white powder in a hard gelatin capsule of size No. 3, opaque dark yellow cap with the inscription "18" and opaque white body with the inscription "mg"; capsules of 25 mg: white powder in a hard gelatin capsule of size No. 3, opaque blue cap with the inscription "25" and opaque white body with the inscription "mg"; capsules of 40 mg: white powder in a hard gelatin capsule of size No. 3, opaque blue cap with the inscription "40" and opaque blue body with the inscription "mg".

Pharmacotherapeutic group

Psychostimulants and nootropics. Central sympathomimetics. Atomoxetine. ATC code N06B A09.

Pharmacological properties

Pharmacodynamics

Mechanism of action and pharmacodynamic effects

Atomoxetine is a highly selective and potent inhibitor of the presynaptic norepinephrine transporter, whose likely mechanism of action is that it has an indirect effect on serotonin and dopamine transporters. Atomoxetine has minimal affinity for other norepinephrine receptors or other neurotransmitter transporters or receptors. Atomoxetine has two main oxidative metabolites - 4-hydroxyatomoxetine and N-desmethylatomoxetine. 4-hydroxyatomoxetine has the same efficacy as atomoxetine as a norepinephrine transporter inhibitor, but, unlike atomoxetine, this metabolite also has some inhibitory activity against the serotonin transporter. However, any effect on this transporter is usually minimal, as most of 4-hydroxyatomoxetine undergoes further metabolism, so it circulates in plasma at significantly lower concentrations (1% of atomoxetine concentration in patients who are fast metabolizers and 0.1% of atomoxetine concentration in patients who are slow metabolizers). N-desmethylatomoxetine has significantly lower pharmacological activity compared to atomoxetine. In the steady state, it circulates in the plasma at lower concentrations in fast metabolizers and at concentrations comparable to those of the original drug in slow metabolizers.

Atomoxetine is not a psychostimulant and is not an amphetamine derivative. In the process of studying the addictive potential in adults, where the effects of atomoxetine and placebo were compared, atomoxetine was not associated with a response model that indicates stimulant or euphoric properties.

Clinical efficacy and safety

Pediatric patients

It is known that atomoxetine was studied in trials involving children and adolescents with attention deficit hyperactivity disorder (ADHD). A statistically significant advantage of atomoxetine over placebo was noted in reducing the symptoms and signs of ADHD, as well as in maintaining a response. After a year of treatment with atomoxetine, patients were less likely to relapse or partially return to symptoms compared to patients who discontinued active treatment and switched to placebo. In children and adolescents, it is necessary to periodically assess the effectiveness of ongoing therapy during long-term treatment.

Atomoxetine was effective both when used once a day and when the dose was divided into two doses - in the morning and after lunch/early evening.

Active comparator study

It is known that in a study aimed at confirming the non-inferiority of atomoxetine compared to standard methylphenidate with prolonged release, the comparator was associated with a higher response rate than atomoxetine.

Adult patients

It is known that the use of atomoxetine was studied in trials involving adult patients diagnosed with ADHD according to the DSM-IV diagnostic criteria. A statistically significant advantage of atomoxetine over placebo was noted in reducing the symptoms and signs of ADHD. In the analysis of clinically significant response in studies, statistically significant higher response rates were consistently noted compared to patients receiving placebo.

It is known that in studies involving patients with ADHD and comorbid alcoholism or social anxiety disorder, a reduction in ADHD symptoms was observed. In a study involving patients who abused alcohol, there was no difference between the atomoxetine and placebo groups in terms of alcohol consumption. In a study involving patients with social anxiety disorder, the use of atomoxetine did not worsen the course of the latter.

It is known that a study demonstrated the efficacy of atomoxetine in maintaining a response to treatment.

QT/QTc interval study

It is known that in a study of the effect on the QT/QTc interval, patients who received atomoxetine had a statistically significantly unchanged QTc interval compared to the placebo group. With an increase in atomoxetine concentration, a slight increase in the QTc interval was observed.

Pharmacokinetics

The pharmacokinetic parameters of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine has not been evaluated in children under 6 years of age.

Absorption

After oral administration, atomoxetine is rapidly and almost completely absorbed, reaching a mean maximum concentration in plasma (Cmax) approximately 1-2 hours after administration. The absolute bioavailability of atomoxetine after oral administration was 63% to 94%, depending on interpatient differences in moderate presystemic metabolism. Atomoxetine can be taken regardless of food intake.

Distribution

Atomoxetine is widely distributed and actively (98%) bound to plasma proteins, mainly albumin.

Metabolism

Atomoxetine undergoes metabolism mainly through the cytochrome P450 2D6 (CYP2D6) enzyme pathway. Individuals with reduced activity of this pathway (slow metabolizers) make up approximately 7% of the Caucasian population and have a higher concentration of atomoxetine in plasma compared to patients with normal activity (fast metabolizers). In slow metabolizers, the area under the pharmacokinetic curve (AUC) of atomoxetine is approximately 10 times higher, and the Css max value is almost 5 times higher than in fast metabolizers. The main oxidative metabolite is 4-hydroxyatomoxetine, which is rapidly glucuronidated. 4-hydroxyatomoxetine has the same activity as atomoxetine, but circulates in plasma at significantly lower concentrations. Although 4-hydroxyatomoxetine is formed mainly under the influence of CYP2D6, in individuals with insufficient CYP2D6 activity, 4-hydroxyatomoxetine may be formed under the influence of several other cytochrome P450 enzymes, but at a lower rate. At therapeutic doses, atomoxetine does not inhibit or induce CYP2D6.

Cytochrome P450 enzymes: atomoxetine did not cause clinically significant inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

Elimination

The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in fast metabolizers and 21 hours in slow metabolizers. Atomoxetine is eliminated mainly in the form of 4-hydroxyatomoxetine O-glucuronide and predominantly with urine.

Linearity/Nonlinearity

The pharmacokinetics of atomoxetine is linear in the studied dose range in both fast and slow metabolizers.

Special populations

Liver dysfunction leads to a decrease in the clearance of atomoxetine, an increase in the AUC of atomoxetine (AUC increases 2-fold with moderate impairment and 4-fold with severe impairment), and an extension of the elimination half-life of the original drug compared to healthy volunteers with the same fast metabolizer CYP2D6 genotype. Patients with moderate or severe liver dysfunction (class B and C according to the Child-Pugh classification) require adjustment of initial and target doses (see "Method of administration and doses").

The mean plasma concentration of atomoxetine in patients with end-stage renal disease (ESRD) was higher than in healthy volunteers, which was confirmed by an increase in Cmax (difference of 7%) and AUC0-∞ (difference of approximately 65%). After adjusting for body weight, the differences between the two groups were minimal. The pharmacokinetics of atomoxetine and its metabolites in patients with ESRD indicate no need for dose adjustment (see "Method of administration and doses").

Clinical characteristics

Indications

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6 years and older, adolescents, and adults as part of a comprehensive treatment program. Treatment should be initiated by a specialist with experience in treating ADHD, such as a pediatrician, child/adolescent psychiatrist, or psychiatrist. The diagnosis should be made according to current DSM criteria (Diagnostic and Statistical Manual of Mental Disorders) or ICD guidelines (International Classification of Diseases).

In adults, it is necessary to confirm the presence of ADHD symptoms that occurred in childhood. It is advisable to involve an unbiased person in the decision-making process, and treatment with atomoxetine should not be started if the presence of ADHD symptoms in childhood is not confirmed. The diagnosis cannot be made solely on the basis of one or more ADHD symptoms. Based on clinical evaluation, patients should have ADHD symptoms of at least moderate severity, which is confirmed by functional impairment of moderate severity in at least 2 areas (e.g., social, academic, and/or professional activities), which affect different aspects of a person's life.

Additional information on the safety of this medicinal product

Comprehensive treatment program

The comprehensive treatment program usually includes psychological, educational, and social measures and is aimed at stabilizing the condition of patients with a behavioral syndrome characterized by symptoms that may include chronic inattention, pathological distraction, emotional lability, impulsivity, moderate or severe hyperactivity, minor neurological signs, and EEG deviations. In some cases, there may be a violation of learning ability.

Pharmacological treatment is indicated not for all patients with this syndrome, so the decision to use a medicinal product should be based on a very careful assessment of the severity of symptoms and the degree of impairment, taking into account the patient's age and the duration of symptoms.

Contraindications

Increased sensitivity to the active substance or to any of the excipients of the medicinal product.

Atomoxetine should not be prescribed in combination with monoamine oxidase inhibitors (MAOIs). Atomoxetine should not be used for at least 2 weeks after discontinuation of MAOI treatment. MAOI treatment should not be started within 2 weeks after discontinuation of atomoxetine.

The medicinal product should not be prescribed to patients with narrow-angle glaucoma, as the use of atomoxetine has been associated with an increased frequency of mydriasis in clinical trials.

Atomoxetine should not be prescribed to patients with severe cardiovascular disorders or cerebrovascular disorders (see "Special warnings and precautions for use"). Severe cardiovascular disorders may include severe hypertension, heart failure, arterial occlusive disease, angina pectoris, hemodynamically significant congenital heart disease, cardiomyopathy, myocardial infarction, potentially life-threatening arrhythmias, and channelopathies (disorders caused by dysfunction of ion channels). Severe cerebrovascular disorders may include aneurysm of the brain or stroke.

Atomoxetine should not be prescribed to patients with existing or a history of pheochromocytoma (see "Special warnings and precautions for use").

Interactions with other medicinal products and other forms of interaction

Effect of other medicinal products on atomoxetine

MAOIs. Atomoxetine should not be used in combination with MAOIs (see "Contraindications").

CYP2D6 inhibitors (SSRIs, e.g., fluoxetine, paroxetine), quinidine, terbinafine. In patients receiving these medicinal products, the AUC of atomoxetine may increase 6-8 times, and the Css max of atomoxetine may increase 3-4 times, as it is metabolized via CYP2D6. Patients who are already taking medicinal products that inhibit CYP2D6 may require a gradual decrease in dose and a final lower dose of atomoxetine. If a CYP2D6 inhibitor is prescribed or discontinued after titrating atomoxetine to an appropriate dose, the patient should be re-evaluated for clinical response and tolerability to determine the need for dose adjustment.

Caution is recommended when combining atomoxetine with potent inhibitors of cytochrome P450 enzymes, other than CYP2D6, in patients who are slow metabolizers of CYP2D6, as the risk of clinically significant increase in AUC of atomoxetine in vivo is unknown.

Salbutamol (or other β2-agonists). Atomoxetine should be prescribed with caution to patients receiving high doses of salbutamol (or other β2-agonists) in aerosol form or by systemic administration, as the effect on the cardiovascular system may increase.

The data on this interaction are conflicting. Systemically administered salbutamol (600 μg IV over 2 hours) in combination with atomoxetine (60 mg twice daily for 5 days) caused an increase in heart rate (HR) and arterial pressure (AP). This effect was most pronounced after initial concomitant administration of salbutamol and atomoxetine but returned to baseline within 8 hours. However, in a separate study involving healthy adult volunteers of Asian descent who were fast metabolizers of atomoxetine, the effect of a standard inhaled dose of salbutamol (200 μg) on AP and HR was not enhanced when administered concomitantly with atomoxetine (80 mg once daily for 5 days). Similarly, after multiple inhalations of salbutamol (800 μg), HR did not change regardless of the presence or absence of atomoxetine.

It is necessary to monitor HR and AP, and in the event of significant changes, adjustment of the dose of atomoxetine or salbutamol (or other β2-agonists) may be justified.

There is a possibility of an increased risk of QT interval prolongation if atomoxetine is used with other medicinal products that prolong the QT interval (such as antipsychotics, antiarrhythmic drugs of class IA and III, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium, or cisapride), with medicinal products that cause electrolyte imbalance (such as thiazide diuretics), and with medicinal products that inhibit CYP2D6.

Seizures are a potential risk of atomoxetine use. Caution is recommended when concomitantly using medicinal products that lower the seizure threshold (such as tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs), antipsychotics, phenothiazines, or butyrophenone, mefloquine, chloroquine, bupropion, or tramadol) (see "Special warnings and precautions for use"). Additionally, due to the risk of seizure, caution is recommended when discontinuing concomitant treatment with benzodiazepines.

Antihypertensive medicinal products. Atomoxetine should be used with caution in combination with antihypertensive medicinal products. Due to the possible increase in AP, atomoxetine may reduce the effectiveness of antihypertensive medicinal products/medicinal products used to treat hypertension. It is necessary to monitor AP, and in the event of significant changes, the treatment regimen with atomoxetine or antihypertensive medicinal products may need to be revised.

Vasoconstrictor medicinal products or medicinal products that increase AP. Due to the possible increase in the effect on AP, atomoxetine should be used with caution in combination with vasoconstrictor medicinal products or medicinal products that may increase AP (e.g., salbutamol). It is necessary to monitor AP, and in the event of significant changes, the treatment regimen with atomoxetine or vasoconstrictor medicinal products may need to be revised.

Medicinal products that affect norepinephrine. Due to the possible additional or synergistic pharmacological effect, atomoxetine should be used with caution in combination with medicinal products that affect norepinephrine (e.g., antidepressants such as imipramine, venlafaxine, and mirtazapine, or decongestants such as pseudoephedrine or phenylephrine).

Medicinal products that affect gastric pH. Medicinal products that increase gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) did not affect the bioavailability of atomoxetine.

Medicinal products that are highly bound to plasma proteins. In vitro studies of drug displacement were conducted for atomoxetine and other medicinal products that are highly bound to plasma proteins at therapeutic concentrations. Warfarin, acetylsalicylic acid, phenytoin, or diazepam did not affect the binding of atomoxetine to human albumin. Similarly, atomoxetine did not affect the binding of these compounds to human albumin.

Special warnings and precautions for use

Suicidal behavior

It is known that in patients who received atomoxetine, there were reports of suicidal behavior (suicide attempts and suicidal thoughts). In double-blind clinical trials, cases of suicidal behavior were rare but more frequent among children and adolescents who received atomoxetine compared to those who received placebo and had no such phenomena. In double-blind clinical trials involving adult patients, there was no difference in the frequency of suicidal behavior between the atomoxetine and placebo groups. Patients who receive treatment for ADHD should be under close supervision to monitor the emergence or worsening of suicidal behavior.

Sudden death and existing heart defects

Reports of sudden death have been received in patients with structural heart defects who took atomoxetine at usual doses. Although only a few serious structural heart defects have an increased risk of sudden death, patients with known serious structural heart defects should be prescribed atomoxetine with caution and after consultation with a cardiologist.

Effect on the cardiovascular system

Atomoxetine may affect HR and AP. Most patients who take atomoxetine experience a slight increase in HR (on average <10 beats/min) and/or an increase in AP (on average <5 mmHg) (see "Adverse reactions").

However, according to clinical trials, in patients with ADHD, more pronounced changes in HR (≥20 beats/min) and AP (≥15-20 mmHg) occur; during atomoxetine treatment, these changes were gradual and persistent. Prolonged persistent changes in AP may potentially lead to clinical consequences such as myocardial hypertrophy.

Therefore, patients who are planned to receive atomoxetine should undergo a thorough medical history and physical examination to detect cardiovascular diseases. If the initial results indicate a relevant history or disease, patients should be further examined by a cardiologist.

It is recommended to measure and record HR and AP before starting treatment, as well as during treatment after each dose adjustment, and then at least every 6 months to detect possible clinically significant increases. For pediatric patients, it is recommended to use a percentile method. For adult patients, current guidelines for hypertension should be followed (see "Special warnings and precautions for use").

Atomoxetine should not be prescribed to patients with severe cardiovascular disorders or cerebrovascular disorders (see "Contraindications"). Atomoxetine should be prescribed with caution to patients with underlying diseases that may worsen due to increased AP and HR, such as patients with hypertension, tachycardia, or cardiovascular diseases or cerebrovascular disorders.

Patients who develop symptoms such as palpitations, chest pain during physical exertion, unexplained syncope, shortness of breath, or other symptoms suggestive of heart disease during atomoxetine treatment should consult a cardiologist.

In addition, atomoxetine should be prescribed with caution to patients with congenital or acquired long QT interval or QT interval prolongation in family history (see "Interactions with other medicinal products and other forms of interaction" and "Adverse reactions").

Since orthostatic hypotension has also been reported, atomoxetine should be used with caution in any conditions that may cause hypotension or in conditions associated with sudden changes in HR or AP.

Cerebrovascular disorders

Patients with additional risk factors for cerebrovascular disorders (such as cardiovascular diseases in history, concomitant medicinal products that increase AP) should be evaluated during each visit for neurological signs and symptoms after starting atomoxetine treatment.

Effect on liver function

Very rarely, liver damage has been reported, manifested by an increase in liver enzyme levels and bilirubin with jaundice. Very rarely, severe liver damage has been reported, including acute liver failure. In patients with jaundice or laboratory signs of liver damage, atomoxetine treatment should be discontinued and not resumed.

Psychotic or manic symptoms

Psychotic or manic symptoms that occur during treatment, such as hallucinations, delusional thinking, mania, or agitation, in patients who do not have a history of psychotic disorders or mania, may be caused by atomoxetine at usual doses. If such symptoms occur, it is necessary to assess the potential relationship with atomoxetine and consider the possibility of discontinuing treatment. It is not excluded that atomoxetine may cause an exacerbation of previously detected psychotic or manic symptoms.

Aggressive behavior, hostility, or emotional lability

In clinical trials, hostility (mostly aggression, oppositional behavior, and anger) was more frequently observed in children, adolescents, and adults who received atomoxetine compared to those who received placebo. In clinical trials, emotional lability was more frequently observed in children who received atomoxetine than in children who received placebo. Patients should be under close supervision to monitor the emergence or worsening of aggressive behavior, hostility, or emotional lability.

Possible allergic reactions

In patients who took atomoxetine, allergic reactions, including anaphylactic reactions, rash, angioedema, and urticaria, occurred with a frequency of "rare".

Eye irritation

Capsules should not be opened. Atomoxetine is an eye irritant. In case of contact of the capsule contents with the eyes, the affected eye should be rinsed with water immediately, and medical attention should be sought. Hands and any potentially contaminated surfaces should be washed as soon as possible.

Seizures

Seizures are a potential risk of atomoxetine use. Atomoxetine should be prescribed with caution to patients with a history of seizures. The possibility of discontinuing atomoxetine should be considered in any patient who experiences a seizure or an increase in seizure frequency without an identified cause.

Growth and development

During atomoxetine treatment, it is necessary to monitor the growth and development of children and adolescents. Patients who require long-term therapy should be under supervision, and in children and adolescents who do not grow or gain weight properly, it is possible to consider reducing the dose or discontinuing therapy.

Clinical data do not indicate a harmful effect of atomoxetine on cognition or sexual maturation; however, the amount of available long-term data is limited. Therefore, it is necessary to closely monitor the condition of patients who require long-term therapy.

Development or worsening of comorbid depression, anxiety, or tics

In a controlled study involving children with ADHD and comorbid chronic motor tics or Tourette's syndrome, patients who received atomoxetine did not experience worsening of tics compared to patients who received placebo. In a controlled study involving adolescents with ADHD and major depressive disorder, patients who received atomoxetine did not experience worsening of depression compared to patients who received placebo. In two controlled studies (one involving children and one involving adults) in patients with ADHD and comorbid anxiety disorders, patients who received atomoxetine did not experience worsening of anxiety compared to patients who received placebo.

There have been rare post-marketing reports of anxiety and depression or mood swings in patients taking atomoxetine (see "Adverse reactions").

Patients who receive atomoxetine for ADHD should be under close supervision to monitor the emergence or worsening of symptoms of anxiety, depression, or tics.

Patients under 6 years of age

Atomoxetine should not be prescribed to patients under 6 years of age, as its efficacy and safety in this age group have not been established (see "Special warnings and precautions for use").

Other therapeutic uses

Atomoxetine is not intended for the treatment of major depressive episodes and/or anxiety, as the results of clinical trials in adults with these conditions without ADHD did not show efficacy compared to placebo (see "Pharmacological properties").

Pregnancy and lactation

Pregnancy

It is known that animal studies did not reveal a negative effect on pregnancy, embryonic development, fetal development, childbirth, or postnatal development. Clinical data on the effect of atomoxetine on pregnancy are limited. These data are insufficient to conclude a relationship between atomoxetine and adverse pregnancy outcomes and/or breastfeeding or the absence of such a relationship. Atomoxetine should be used during pregnancy only when the expected benefit outweighs the potential risk to the fetus.

Breastfeeding

Atomoxetine and/or its metabolites are excreted in the milk of rats. It is not known whether atomoxetine passes into human breast milk. Due to the lack of data, atomoxetine should be avoided during breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery

Data on the effect of the medicinal product on reaction speed when driving vehicles or operating machinery are limited. Atomoxetine has a minimal effect on the ability to drive a vehicle and operate machinery. In children and adults, atomoxetine was associated with increased fatigue, drowsiness, and dizziness compared to placebo. Patients are advised to be cautious when driving a vehicle and operating machinery until they are sure that atomoxetine does not affect their performance.

Method of administration and doses

Doses

Atomoxetine can be taken in the morning as a single daily dose. Patients who do not achieve a satisfactory clinical response (tolerability, e.g., in case of nausea or drowsiness, or efficacy) when taking atomoxetine as a single daily dose may benefit from taking the medicinal product twice daily in divided doses in the morning and after lunch/early evening.

Pediatric patients

Dose selection for pediatric patients with a body weight of less than 70 kg:

Treatment with atomoxetine should be initiated with a total daily dose of approximately 0.5 mg/kg. This dose should be taken for at least 7 days before increasing the dose based on clinical response and tolerability. The recommended maintenance dose is approximately 1.2 mg/kg/day (depending on the patient's body weight and available atomoxetine dosages). When using doses exceeding 1.2 mg/kg/day, no additional benefit was observed. The safety of single doses exceeding 1.8 mg/kg/day and total daily doses exceeding 1.8 mg/kg has not been systematically evaluated. In some cases, continuation of treatment into adulthood may be justified.

Dose selection for pediatric patients with a body weight of 70 kg or more:

Treatment with atomoxetine should be initiated with a total daily dose of 40 mg. This dose should be taken for at least 7 days before increasing the dose based on clinical response and tolerability. The recommended maintenance dose is 80 mg. When using doses exceeding 80 mg, no additional benefit was observed. The maximum recommended total daily dose is 100 mg. The safety of single doses exceeding 120 mg and total daily doses exceeding 150 mg has not been systematically evaluated.

Adult patients

Treatment with atomoxetine should be initiated with a total daily dose of 40 mg. This dose should be taken for at least 7 days before increasing the dose based on clinical response and tolerability. The maximum recommended daily dose is 80-100 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses exceeding 120 mg and total daily doses exceeding 150 mg has not been systematically evaluated.

Additional information on the safety of this medicinal product

Prior examination

Before prescribing treatment, it is necessary to collect relevant medical history and perform a basic assessment of the patient's cardiovascular function, including measurement of AP and HR (see "Interactions with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Ongoing monitoring

It is necessary to regularly assess the patient's cardiovascular function, measuring AP and HR after each dose adjustment, and then every 6 months. For pediatric patients, it is recommended to use a percentile method. For adult patients, current guidelines for hypertension should be followed (see "Special warnings and precautions for use").

Discontinuation of treatment

In the course of studies, no pronounced withdrawal symptoms were described. In the event of significant adverse reactions, atomoxetine can be discontinued abruptly or the dose of the medicinal product can be gradually decreased over a suitable period.

Treatment with atomoxetine should not be long-term. After 1 year of treatment, it is necessary to re-evaluate the need for continued therapy, especially when the patient has achieved a sustained satisfactory response.

Special populations

Elderly patients

The use of atomoxetine in patients aged 65 years and older has not been systematically evaluated.

Liver dysfunction

For patients with moderate liver dysfunction (class B according to the Child-Pugh classification), the initial and target doses should be reduced to 50% of the usual dose. For patients with severe liver dysfunction (class C according to the Child-Pugh classification), the initial dose and target doses should be reduced to 25% of the usual dose (see "Pharmacological properties").

Kidney dysfunction

In patients with end-stage renal disease (ESRD), the systemic exposure of atomoxetine was higher than in healthy subjects (approximately 65% higher), but when exposure was adjusted for dose (mg/kg), the difference was minimal. Therefore, patients with ADHD and ESRD or lesser degrees of kidney dysfunction may be prescribed atomoxetine at standard doses. Atomoxetine may exacerbate hypertension in patients with ESRD (see "Pharmacological properties").

Patients with kidney dysfunction

Approximately 7% of the Caucasian population has a genotype corresponding to a non-functional CYP2D6 enzyme (such individuals are called slow metabolizers of CYP2D6). In patients with this genotype, exposure to atomoxetine is several times higher than in patients with a functional enzyme. Therefore, slow metabolizers are at high risk of adverse reactions (see "Pharmacological properties" and "Adverse reactions"). For patients with a known slow metabolizer genotype, it is possible to consider prescribing a lower initial dose and gradual dose increase.

Method of administration

For oral administration. Atomoxetine can be taken regardless of food intake.

Capsules should not be opened, and the contents of the capsules should not be removed and taken in any other way.

Children

The safety and efficacy of atomoxetine in children and adolescents under 6 years of age have not been established, so the medicinal product should not be prescribed to children in this age group (see "Special warnings and precautions for use").

Overdose

Signs and symptoms

It is known that in the post-marketing period, there were reports of non-fatal cases of acute and chronic overdose of atomoxetine after its use as monotherapy. The most common symptoms that accompanied acute and chronic overdose were gastrointestinal disorders, drowsiness, dizziness, tremor, and behavioral disorders. Additionally, there were reports of hyperactivity and agitation. Also, signs and symptoms that corresponded to mild or moderate activation of the autonomic nervous system (e.g., tachycardia, increased AP, mydriasis, dry mouth) were observed, as well as reports of pruritus and rash. Most cases were mild or moderate in severity. In some cases of overdose associated with atomoxetine, there were reports of epileptiform seizures, very rarely - QT interval prolongation. Also, there were reports of fatal cases due to acute overdose associated with the concomitant use of atomoxetine and at least one other medicinal product.

Treatment

It is necessary to ensure adequate ventilation of the lungs. Within 1 hour after overdose, activated charcoal can be used to reduce absorption. It is recommended to monitor cardiac activity and vital signs, as well as to apply appropriate symptomatic and supportive measures. The patient should be under supervision for at least 6 hours. Since atomoxetine is highly bound to proteins, treatment of overdose by dialysis is likely to be ineffective.

Adverse Reactions

Through decreased appetite in the early stages of therapy, a delay in the increase in body mass and growth was noted. On average, after the initial decrease in body weight and growth in patients receiving atomoxetine, an increase to average norms was observed, as expected based on group baseline data during long-term treatment.

Nausea, vomiting, and somnolence2 may occur in approximately 10-11% of patients, especially during the first month of therapy. However, these episodes were usually mild or moderate in severity and temporary in nature and did not lead to discontinuation of treatment in a significant number of cases (the frequency of discontinuation of therapy is ≤ 0.5%).

In the process of placebo-controlled studies involving both children and adults, an increase in heart rate, systolic and diastolic blood pressure was observed in patients taking atomoxetine (see the section "Special Instructions").

Due to the effect on noradrenergic tone in patients receiving atomoxetine, orthostatic hypotension (0.2%) and syncope (0.8%) were observed. Atomoxetine should be prescribed with caution to patients with conditions that can cause the development of orthostatic hypotension.

The following adverse reactions are based on reports of adverse events and laboratory study results conducted during clinical trials, as well as on spontaneous post-registration reports of use in children and adolescents.

Frequency categories: very often (≥ 1/10), often (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1,000 to < 1/100), rare (from ≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Metabolic and Nutritional Disorders

Very often - decreased appetite; often - anorexia (loss of appetite).

Psychiatric Disorders

Often - irritability, mood swings, insomnia3, excitement*, anxiety, depression, and decreased mood*, tics*; uncommon - suicidal behavior, aggression, hostility, emotional lability*, psychosis (including hallucinations)*.

Nervous System Disorders

Very often - headache, somnolence2; often - dizziness; uncommon - syncope, tremor, migraine, paresthesia*, hypoesthesia*; rare - seizures**.

Eye Disorders

Often - mydriasis; uncommon - blurred vision.

Cardiac Disorders

Uncommon - tachycardia, sinus tachycardia, QT interval prolongation**.

Vascular Disorders

Rare - Raynaud's disease.

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon - dyspnea (see the section "Special Instructions").

Gastrointestinal Disorders

Very often - abdominal pain1, vomiting, nausea; often - constipation, dyspepsia.

Hepatobiliary Disorders

Uncommon - elevated bilirubin levels in the blood*; rare - pathological levels/elevation of liver enzymes, jaundice, hepatitis, liver damage, acute liver failure*.

Skin and Subcutaneous Tissue Disorders

Often - dermatitis, pruritus, rash; uncommon - hyperhidrosis, allergic reactions.

Renal and Urinary Disorders

Rare - urinary retention, urinary hesitation.

Reproductive System and Breast Disorders

Rare - priapism, genital pain in male patients.

General Disorders and Administration Site Conditions

Often - fatigue, apathy, chest pain (see the section "Special Instructions"); uncommon - asthenia.

Laboratory and Instrumental Investigations

Very often - elevated blood pressure4, increased heart rate4; often - decreased body weight.

1Also includes upper abdominal pain, discomfort in the stomach, abdominal discomfort, and discomfort in the epigastrium.

2Also includes sedation.

3Includes sleep disturbances, nighttime sleep disturbances, and early morning awakening.

4The results of heart rate and blood pressure indicators are given according to the baseline vital signs.

*See the section "Special Instructions".

**See the sections "Interaction with Other Medicinal Products and Other Types of Interactions" and "Special Instructions".

Slow Metabolizers (SM) CYP2D6

The following adverse reactions were observed in at least 2% of patients who are slow metabolizers (SM) CYP2D6, and their frequency was statistically significantly higher in SM patients compared to patients who are fast metabolizers (FM) CYP2D6: decreased appetite (24.1% SM, 17% FM); insomnia complex (including insomnia, sleep disturbances, sleep disorders, 14.9% SM, 9.7% FM); depression complex (including depression, major depressive disorder, symptoms of depression, decreased mood, and dysphoria, 6.5% SM and 4.1% FM), decreased body weight (7.3% SM, 4.4% FM), constipation (6.8% SM, 4.3% FM), tremor (4.5% SM, 0.9% FM), sedation (3.9% SM, 2.1% FM), dry mouth (3.9% SM, 1.7% FM), enuresis (3% SM, 1.2% FM), conjunctivitis (2.5% SM, 1.2% FM), syncope (2.5% SM, 0.7% FM), early morning awakening (2.3% SM, 0.8% FM), mydriasis (2% SM, 0.6% FM). The following phenomenon did not meet the defined criteria but deserves mention: generalized anxiety disorder (0.8% SM and 0.1% FM). Additionally, in trials that lasted up to 10 weeks, weight loss was more pronounced in SM patients (on average 0.6 kg in FM and 1.1 kg in SM).

Adults

Brief Description of the Safety Profile

In clinical trials in which adult patients with ADHD participated, the frequency of adverse reactions during atomoxetine treatment was highest in the following system-organ classes: gastrointestinal disorders, nervous system disorders, and psychiatric disorders. The most common (≥ 5%) adverse reactions reported were decreased appetite (14.9%), insomnia (11.3%), headache (16.3%), dry mouth (18.4%), and nausea (26.7%). Most of these events were mild or moderate in severity, and the most common adverse reactions of severe severity were nausea, insomnia, fatigue, and headache. Complaints of urinary retention or difficulty urinating in adults should be considered as potentially related to the use of atomoxetine.

The following adverse reactions are based on reports of adverse events and laboratory study results conducted during clinical trials, as well as on spontaneous post-registration reports of use in adults.

Frequency categories: very often (≥ 1/10), often (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1,000 to < 1/100), rare (from ≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Metabolic and Nutritional Disorders

Very often - decreased appetite.

Psychiatric Disorders

Very often - insomnia2; often - excitement*, decreased libido, sleep disorders, depression, and decreased mood*, anxiety; uncommon - suicidal behavior*, aggression, hostility, and emotional lability*, anxiety, tics*; rare - psychosis (including hallucinations)*.

Nervous System Disorders

Very often - headache; often - dizziness, taste disturbances, paresthesia, somnolence (including sedation), tremor; uncommon - syncope, migraine, hypoesthesia*; rare - seizures**.

Eye Disorders

Uncommon - blurred vision.

Cardiac Disorders

Often - tachycardia, palpitations; uncommon - QT interval prolongation**.

Vascular Disorders

Often - hyperemia, flushing; uncommon - cold extremities; rare - Raynaud's disease.

Respiratory, Thoracic, and Mediastinal Disorders

Uncommon - dyspnea (see the section "Special Instructions").

Gastrointestinal Disorders

Very often - dry mouth, nausea; often - abdominal pain1, constipation, dyspepsia, flatulence, vomiting.

Hepatobiliary Disorders

Rare - pathological levels/elevation of liver enzymes, jaundice, hepatitis, liver damage, acute liver failure, elevated bilirubin levels in the blood*.

Skin and Subcutaneous Tissue Disorders

Often - dermatitis, hyperhidrosis, rash; uncommon - allergic reactions4, pruritus, urticaria.

Musculoskeletal and Connective Tissue Disorders

Uncommon - muscle spasms.

Renal and Urinary Disorders

Often - dysuria, pollakiuria, urinary retention, urinary hesitation; uncommon - urination urgency.

Reproductive System and Breast Disorders

Often - dysmenorrhea, ejaculation disorder, erectile dysfunction, prostatitis, genital pain in male patients; uncommon - ejaculation failure, irregular menstrual cycle, orgasm disorder; rare - priapism.

General Disorders and Administration Site Conditions

Often - asthenia, fatigue, apathy, chills, feeling of unease, irritability; uncommon - feeling of cold, chest pain (see the section "Special Instructions").

Laboratory and Instrumental Investigations

Very often - elevated blood pressure3, increased heart rate3; often - decreased body weight.

1Also includes upper abdominal pain, discomfort in the stomach, abdominal discomfort, and discomfort in the epigastrium.

2Includes sleep disturbances, nighttime sleep disturbances, and early morning awakening.

3The results of heart rate and blood pressure indicators are given according to the baseline vital signs.

4Includes anaphylactic reactions and angioedema.

*See the section "Special Instructions".

**See the sections "Interaction with Other Medicinal Products and Other Types of Interactions" and "Special Instructions".

Slow Metabolizers (SM) CYP2D6

The following adverse reactions were observed in at least 2% of patients who are slow metabolizers (SM) CYP2D6, and their frequency was statistically significantly higher in SM patients compared to patients who are fast metabolizers (FM) CYP2D6: blurred vision (3.9% SM, 1.3% FM), dry mouth (34.5% SM, 17.4% FM), constipation (11.3% SM, 6.7% FM), feeling of unease (4.9% SM, 1.9% FM), decreased appetite (23.2% SM, 14.7% FM), tremor (5.4% SM, 1.2% FM), insomnia (19.2% SM, 11.3% FM), sleep disorders (6.9% SM, 3.4% FM), sleep disturbances (5.4% SM, 2.7% FM), early morning awakening (3% SM, 0.9% FM), urinary retention (5.9% SM, 1.2% FM), erectile dysfunction (20.9% SM, 8.9% FM), ejaculation disorder (6.1% SM, 2.2% FM), hyperhidrosis (14.8% SM, 6.8% FM), cold extremities (3% SM, 0.5% FM).

Shelf Life

3 years.

Storage Conditions

Store in the original packaging in a place inaccessible to children. No special storage conditions are required.

Packaging

For 10 mg capsules: 7 capsules in a blister pack; 1 blister pack in a carton.

For 18 mg, 25 mg, and 40 mg capsules: 7 capsules in a blister pack; 1 or 2 blister packs in a carton.

Release Category

By prescription.

Manufacturer

PHARMATHEN INTERNATIONAL S.A.

PHARMATHEN S.A.

Manufacturer's Location and Address of Business

Industrial Park Sapes, Prefecture Rodopi, Block No. 5, Rodopi 69300, Greece.

Dervenakion 6, Pallini Attica 15351, Greece.