Atomoxetine®

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

Composition:

Active ingredient: 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, equivalent to 10 mg or 18 mg or 25 mg or 40 mg of atomoxetine;

Excipients: pregelatinized maize starch (starch 1500), colloidal anhydrous silicon dioxide, simethicone (350);

Capsule shell composition:

for 10 mg capsules: gelatin, sodium lauryl sulfate (E 487), titanium dioxide (E 171), purified water;

for 18 mg capsules: gelatin, sodium lauryl sulfate (E 487), titanium dioxide (E 171), yellow iron oxide (E 172), purified water;

for 25 mg and 40 mg capsules: gelatin, sodium lauryl sulfate (E 487), titanium dioxide (E 171), indigo carmine (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 physicochemical properties:

10 mg capsules: white powder in a hard gelatin capsule size № 3, opaque white cap marked with «10» and opaque white body marked with «mg»;

18 mg capsules: white powder in a hard gelatin capsule size № 3, opaque dark yellow cap marked with «18» and opaque white body marked with «mg»;

25 mg capsules: white powder in a hard gelatin capsule size № 3, opaque blue cap marked with «25» and opaque white body marked with «mg»;

40 mg capsules: white powder in a hard gelatin capsule size № 3, opaque blue cap marked with «40» and opaque blue body marked with «mg».

Pharmacotherapeutic group. Psychostimulants and nootropics. Central-acting 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, with its likely mechanism of action being indirect effects on serotonin and dopamine transporters. Atomoxetine has minimal affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors. Atomoxetine has two major oxidative metabolites – 4-hydroxyatomoxetine and N-desmethylatomoxetine. 4-Hydroxyatomoxetine has similar potency to atomoxetine as a norepinephrine transporter inhibitor, but, unlike atomoxetine, this metabolite also has some inhibitory activity on the serotonin transporter. However, any effect on this transporter is generally minimal, as most of the 4-hydroxyatomoxetine undergoes further metabolism and thus circulates in plasma at much lower concentrations (1% of the atomoxetine concentration in patients who are rapid metabolizers, and 0.1% of the atomoxetine concentration in patients who are poor metabolizers). N-desmethylatomoxetine has significantly lower pharmacological activity compared to atomoxetine. At steady state, it circulates in plasma at lower concentrations in rapid metabolizers and at concentrations comparable to those of the parent drug in poor metabolizers.

Atomoxetine is not a psychostimulant and is not an amphetamine derivative. In studies assessing abuse potential in adults comparing the effects of atomoxetine and placebo, atomoxetine was not associated with a response pattern indicating stimulant or euphoriant properties.

Clinical efficacy and safety

Pediatric patients

Atomoxetine has been studied in clinical trials involving children and adolescents with attention deficit hyperactivity disorder (ADHD). Statistically significant superiority of atomoxetine over placebo has been demonstrated in reducing symptoms and signs of ADHD, as well as in maintaining response. After one year of treatment with atomoxetine, patients were less likely to experience relapse or partial return of symptoms compared to patients who discontinued active treatment and switched to placebo. In children and adolescents, the continued effectiveness of long-term therapy should be periodically reassessed.

Atomoxetine was effective both when administered once daily and when the dose was divided into two doses – morning and afternoon/evening.

Studies with active comparator

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

Adult patients

The use of atomoxetine has been studied in clinical trials involving adult patients diagnosed according to DSM-IV criteria for ADHD. A statistically significant advantage of atomoxetine over placebo in reducing symptoms and signs of ADHD has been demonstrated. In analyses of clinically meaningful response, statistically significantly higher response rates were consistently observed compared to patients receiving placebo.

It is known that in studies involving patients with ADHD and comorbid alcohol dependence or social anxiety disorder, improvement in ADHD symptoms was observed. In a study involving patients with alcohol abuse, no difference in alcohol consumption was observed between the atomoxetine and placebo groups. In a study involving patients with social anxiety disorder, treatment with atomoxetine did not worsen the course of the disorder.

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

QT/QTc interval prolongation studies

It is known that in a study assessing the effect on the QT/QTc interval, the QTc interval with atomoxetine was not statistically significantly different from that in the placebo group. A slight increase in QTc interval was observed with increasing atomoxetine concentration.

Pharmacokinetics.

The pharmacokinetic parameters of atomoxetine in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine have 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 plasma concentration (Cmax) approximately 1–2 hours after dosing. The absolute bioavailability of atomoxetine after oral administration ranges from 63% to 94%, depending on inter-individual differences in moderate presystemic metabolism. Atomoxetine can be administered independently of food intake.

Distribution

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

Biotransformation

Atomoxetine undergoes biotransformation primarily via the cytochrome P450 2D6 (CYP2D6) enzyme pathway. Individuals with reduced activity of this pathway (poor metabolizers) constitute approximately 7% of the Caucasian population and have higher plasma concentrations of atomoxetine compared to those with normal activity (extensive metabolizers). In poor metabolizers, the area under the plasma concentration-time curve (AUC) of atomoxetine is approximately 10 times higher, and the Css max is nearly 5 times higher than in extensive metabolizers. The primary oxidative metabolite is 4-hydroxyatomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine has similar activity to atomoxetine but circulates in plasma at significantly lower concentrations. Although 4-hydroxyatomoxetine is formed predominantly by CYP2D6, in individuals with deficient CYP2D6 activity, it may be formed by several other cytochrome P450 enzymes, albeit at a lower rate. At therapeutic doses, atomoxetine does not inhibit or induce CYP2D6.

Cytochrome P450 enzymes: atomoxetine does 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 extensive metabolizers and 21 hours in poor metabolizers. Atomoxetine is eliminated primarily as 4-hydroxyatomoxetine O-glucuronide, predominantly in urine.

Linearity/non-linearity

The pharmacokinetics of atomoxetine are linear over the studied dose range in both extensive and poor metabolizers.

Special populations

Hepatic impairment leads to reduced clearance of atomoxetine, increased AUC of atomoxetine (AUC increases twofold with moderate impairment and fourfold with severe impairment), and prolonged elimination half-life of the parent drug compared to healthy volunteers with the same CYP2D6 extensive metabolizer genotype. Patients with moderate or severe hepatic impairment (Child-Pugh class B and C) require adjustment of initial and target doses (see section "Dosage and administration").

Mean plasma concentrations of atomoxetine in patients with end-stage renal disease (ESRD) were generally higher than in healthy volunteers, as confirmed by increased Cmax (7% difference) and AUC0–∞ (approximately 65% difference). After correction for body weight, 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 section "Dosage and administration").

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 experienced in the management of ADHD, such as a pediatrician, child/adolescent psychiatrist, or psychiatrist. Diagnosis must be established according to current DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria or guidelines from the ICD (International Classification of Diseases).

In adults, the presence of ADHD symptoms that originated in childhood must be confirmed. It is advisable to involve an impartial third party in the decision-making process. Treatment with atomoxetine should not be initiated if childhood ADHD symptoms are not confirmed. Diagnosis cannot be based solely on the presence of one or several ADHD symptoms. Based on clinical assessment, patients must exhibit ADHD symptoms of at least moderate severity, confirmed by functional impairment of at least moderate degree in two or more domains (e.g., social, academic, and/or occupational functioning), affecting various aspects of life.

Additional information on safety of use of this medicinal product

A comprehensive treatment program typically includes psychological, educational, and social measures, aimed at stabilizing patients with a behavioral syndrome characterized by symptoms that may include chronic inattention, pathological distractibility, emotional lability, impulsivity, mild to severe hyperactivity, minor neurological signs, and EEG abnormalities. In some cases, learning disabilities may also be present.

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Atomoxetine must not be used in combination with monoamine oxidase inhibitors (MAOIs). Atomoxetine must not be administered for at least 2 weeks after discontinuation of MAOI therapy. MAOI therapy must not be initiated within 2 weeks after discontinuation of atomoxetine.

The medicinal product must not be prescribed to patients with narrow-angle glaucoma, as clinical trials have shown that atomoxetine use is associated with an increased incidence of mydriasis.

Atomoxetine must not be prescribed to patients with severe cardiovascular disorders or cerebrovascular disorders (see section "Special 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, life-threatening arrhythmia, and channelopathies (disorders caused by dysfunction of ion channels). Severe cerebrovascular disorders may include cerebral aneurysm or stroke.

Atomoxetine must not be prescribed to patients with current or past history of pheochromocytoma (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on atomoxetine

MAOIs. Atomoxetine must not be used concomitantly with MAOIs (see section "Contraindications").

Inhibitors of CYP2D6 (SSRIs (e.g., fluoxetine, paroxetine), quinidine, terbinafine). In patients receiving these medicinal products, the AUC of atomoxetine may increase 6–8 fold, and the Css max may increase 3–4 fold, as it is metabolized via CYP2D6. Patients already taking medicinal products that inhibit CYP2D6 may require a slower dose titration and a lower final dose of atomoxetine. If a CYP2D6 inhibitor is initiated or discontinued after titration of atomoxetine to an appropriate dose, the patient's clinical response and tolerability should be re-evaluated to determine whether dose adjustment is necessary.

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

Salbutamol (or other β2-agonists). Atomoxetine should be used with caution in patients receiving high doses of salbutamol (or other β2-agonists) via aerosol or systemic administration, as cardiovascular effects may be potentiated.

Data on this interaction are conflicting. Systemically administered salbutamol (600 mcg IV over 2 hours) in combination with atomoxetine (60 mg twice daily for 5 days) caused increases in heart rate (HR) and blood pressure (BP). This effect was most pronounced after initial co-administration of salbutamol and atomoxetine, but parameters returned to baseline within 8 hours. However, in a separate study involving healthy adult volunteers of Asian origin who were rapid metabolizers of atomoxetine, short-term co-administration of atomoxetine (80 mg once daily for 5 days) did not potentiate the effects of a standard inhaled dose of salbutamol (200 mcg) on BP and HR. Similarly, after multiple inhalations of salbutamol (800 mcg), HR did not change regardless of the presence or absence of atomoxetine.

HR and BP should be monitored, and dose adjustment of atomoxetine or salbutamol (or other β2-agonists) may be justified in case of significant increases in HR and BP during concomitant use.

There is a potential risk of QT interval prolongation when atomoxetine is used concomitantly with other medicinal products that prolong the QT interval (such as neuroleptics, class IA and III antiarrhythmics, moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium, or cisapride), with medicinal products causing electrolyte imbalances (such as thiazide diuretics), and with medicinal products that inhibit CYP2D6.

Seizures are a potential risk with atomoxetine use. Caution is recommended when co-administering medicinal products that lower the seizure threshold (such as tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRIs), neuroleptics, phenothiazines or butyrophenones, mefloquine, chloroquine, bupropion, or tramadol) (see section "Special precautions for use"). In addition, due to the risk of seizure occurrence, caution is recommended when discontinuing concomitant benzodiazepine therapy.

Antihypertensive medicinal products. Atomoxetine should be used with caution with antihypertensive medicinal products. Because of the potential for increased BP, atomoxetine may reduce the effectiveness of antihypertensive medicinal products or medicinal products used to treat hypertension. BP should be monitored, and if significant changes occur, the treatment regimen with atomoxetine or antihypertensive medicinal products may need to be reconsidered.

Vasopressor medicinal products or medicinal products that increase BP. Due to the potential for increased effects on BP, atomoxetine should be used cautiously with vasopressor medicinal products or medicinal products that may increase BP (e.g., with salbutamol). BP should be monitored, and if significant changes occur, the treatment regimen with atomoxetine or vasopressor medicinal products may need to be reconsidered.

MEDICINAL PRODUCTS AFFECTING NORADRENALINE. Due to the potential for additive or synergistic pharmacological effects, atomoxetine should be used with caution in combination with medicinal products affecting noradrenaline (e.g., antidepressants such as imipramine, venlafaxine, and mirtazapine, or decongestants such as pseudoephedrine or phenylephrine).

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

MEDICINAL PRODUCTS HIGHLY BOUND TO PLASMA PROTEINS. In vitro studies on 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.

Serotonergic agents. Atomoxetine should be used with caution in combination with serotonergic medicinal products, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), opioids such as tramadol, and tetracyclic or tricyclic antidepressants, as the risk of serotonin syndrome, a potentially life-threatening condition, is increased (see section "Special precautions for use").

Special precautions for use.

Suicidal behavior

Suicidal behavior (suicide attempts and suicidal thoughts) has been reported in patients treated with atomoxetine. In double-blind clinical trials, suicidal behavior was infrequent but occurred more often in children and adolescents receiving atomoxetine compared to those receiving placebo, in whom such events were absent. In double-blind clinical trials involving adult patients, no difference in the frequency of suicidal behavior was observed between the atomoxetine and placebo groups. Patients being treated for ADHD should be closely monitored for the emergence or worsening of suicidal behavior.

Serotonin syndrome

Serotonin syndrome has been reported following concomitant use of atomoxetine with other serotonergic medicinal products (e.g., serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), other serotonergic agents, triptans, opioids, as well as tricyclic and tetracyclic antidepressants). If concomitant use of atomoxetine with serotonergic medicinal products is justified, prompt recognition of symptoms of serotonin syndrome is essential. These symptoms may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing therapy depending on the severity of symptoms.

Sudden death and pre-existing cardiac conditions

Sudden death has been reported in patients with structural cardiac abnormalities who were taking atomoxetine at usual doses. Although only certain serious structural cardiac abnormalities are associated with an increased risk of sudden death, atomoxetine should be used with caution in patients with known serious structural cardiac abnormalities and only after consultation with a cardiologist.

Effects on the cardiovascular system

Atomoxetine may affect heart rate (HR) and blood pressure (BP). Most patients taking atomoxetine experience a slight increase in HR (on average < 10 bpm) and/or an increase in BP (on average < 5 mm Hg) (see section "Adverse reactions").

However, according to clinical trials, more pronounced changes in HR (≥ 20 beats per minute) and BP (≥ 15–20 mm Hg) occur in patients with ADHD; during atomoxetine treatment, these changes were gradual and sustained. Sustained, persistent changes in BP may potentially lead to clinical consequences such as myocardial hypertrophy.

Therefore, patients planned for treatment with atomoxetine should undergo a thorough medical history and physical examination to identify any pre-existing cardiac disease. If initial findings suggest relevant history or disease, patients should be further evaluated by a cardiologist.

It is recommended to measure and record HR and BP before initiating treatment, after each dose adjustment during therapy, and thereafter at least every 6 months to detect any potentially clinically significant increases. For pediatric patients, the use of percentile charts is recommended. For adult patients, current guidelines for hypertension should be followed.

Atomoxetine should not be prescribed to patients with severe cardiovascular disorders or cerebrovascular disorders (see section "Contraindications"). Atomoxetine should be used with caution in patients whose underlying conditions may be exacerbated by increased BP and HR, such as patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disorders.

Patients who develop symptoms such as palpitations, chest pain during physical exertion, unexplained syncope, dyspnea, or other symptoms suggestive of cardiac disease during treatment with atomoxetine should seek consultation with a cardiologist.

Furthermore, atomoxetine should be used with caution in patients with congenital or acquired long QT interval or a family history of prolonged QT interval (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

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

Cerebrovascular disorders

Patients with additional risk factors for cerebrovascular disorders (such as a history of cardiovascular disease, concomitant medications that increase BP) should be evaluated at each visit for neurological signs and symptoms following the initiation of atomoxetine treatment.

Effects on liver function

Liver injury, manifested by elevated levels of liver enzymes and bilirubin with jaundice, has been reported very rarely. Severe liver injury, including acute liver failure, has also been reported very rarely. In patients with jaundice or laboratory signs of liver injury, treatment with atomoxetine should be discontinued and not restarted.

Psychotic or manic symptoms

Psychotic or manic symptoms occurring during treatment, such as hallucinations, delusional thinking, mania, or agitation, in patients without a history of psychotic disorders or mania, may be caused by atomoxetine at usual doses. If such symptoms occur, the potential relationship to atomoxetine should be evaluated, and discontinuation of treatment should be considered. There is also a possibility that atomoxetine may exacerbate previously identified psychotic or manic symptoms.

Aggressive behavior, hostility, or emotional lability

In clinical trials, hostility (primarily aggression, oppositional behavior, and anger) was observed more frequently in children, adolescents, and adults receiving atomoxetine compared to those receiving placebo. Emotional lability was observed more frequently in children receiving atomoxetine than in children receiving placebo. Patients should be closely monitored for the emergence or worsening of aggressive behavior, hostility, or emotional lability.

Severe cases have been reported in pediatric patients, including reports of physical violence, threatening behavior, and thoughts of harming others. Families and caregivers of pediatric patients receiving atomoxetine should be advised to contact a physician immediately if significant changes in mood or behavior patterns are observed, especially after initiation of treatment or dose adjustment. Physicians should evaluate the need for dose adjustment or discontinuation of treatment in patients who exhibit behavioral changes.

Possible allergic reactions

Allergic reactions, including anaphylactic reactions, rash, angioedema, and urticaria, occurred with "uncommon" frequency in patients taking atomoxetine.

Eye irritant

Capsules must not be opened. Atomoxetine is an eye irritant. If capsule contents come into contact with the eyes, the affected eye should be rinsed immediately with water and medical advice sought. Hands and any potentially contaminated surfaces should be washed as soon as possible.

Seizures

Seizures are a potential risk associated with the use of atomoxetine. Atomoxetine should be prescribed with caution in patients with a history of seizures. Discontinuation of atomoxetine should be considered in any patient who experiences a seizure or in whom an increase in seizure frequency without an identified cause is observed.

Growth and development

Growth and development of children and adolescents should be monitored during treatment with atomoxetine. Patients requiring long-term therapy should be under observation, and in children and adolescents who are not growing or gaining weight appropriately, consideration should be given to 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, patients requiring long-term therapy should be carefully monitored.

Emergence 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 receiving atomoxetine did not experience worsening of tics compared to those receiving placebo. In a controlled study involving adolescents with ADHD and major depressive disorder, patients receiving atomoxetine did not experience worsening of depression compared to those receiving placebo. In two controlled studies (one involving children and one involving adults) in patients with ADHD and comorbid anxiety disorders, patients receiving atomoxetine did not experience worsening of anxiety compared to those receiving placebo.

Rare post-marketing reports of anxiety, depression, or mood depression, and isolated reports of tics have been received in patients taking atomoxetine (see section "Adverse reactions").

Patients receiving atomoxetine for ADHD should be closely monitored for the emergence or worsening of symptoms of anxiety, mood depression, 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.

Other therapeutic uses

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

Use during pregnancy or breastfeeding.

Pregnancy

Animal studies have not shown adverse effects on pregnancy, embryonal or fetal development, parturition, or postnatal development. Clinical data on the effect of atomoxetine during pregnancy are limited. These data are insufficient to determine whether there is an association between atomoxetine and adverse pregnancy outcomes and/or breastfeeding, or whether such an association is absent. Atomoxetine should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus.

Breastfeeding period

Atomoxetine and/or its metabolites are excreted into the milk of rats. It is unknown whether atomoxetine passes into human breast milk. Due to the insufficient amount of data, use of atomoxetine during breastfeeding should be avoided.

Ability to influence 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 minimal effect on the ability to drive vehicles or operate machinery. In children and adults, atomoxetine has been associated with increased fatigue, somnolence, and dizziness compared to placebo. Patients are advised to exercise caution when driving a car or operating hazardous machinery until they are certain that atomoxetine does not affect their performance.

Dosage and Administration.

Doses

Atomoxetine® may be taken once daily in the morning. Patients who do not achieve satisfactory clinical response (tolerability, e.g., nausea or somnolence, or efficacy) when taking Atomoxetine® as a single daily dose may benefit from twice-daily dosing with evenly divided doses in the morning and afternoon or early evening.

Pediatric patients

Dose selection for pediatric patients with body weight below 70 kg:

Treatment with Atomoxetine® should be initiated at a total daily dose of approximately 0.5 mg/kg. This dose should be maintained for at least 7 days prior to increasing the dose based on clinical response and tolerability. The recommended maintenance dose is approximately 1.2 mg/kg/day (depending on patient's body weight and available atomoxetine strengths). No additional benefit has been observed with doses exceeding 1.2 mg/kg/day. The safety of single doses above 1.8 mg/kg/day and total daily doses above 1.8 mg/kg has not been systematically evaluated. In some cases, continuing treatment into adulthood may be appropriate.

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

Treatment with Atomoxetine® should be initiated at a total daily dose of 40 mg. This dose should be maintained for at least 7 days prior to increasing the dose based on clinical response and tolerability. The recommended maintenance dose is 80 mg. No additional benefit has been observed with doses exceeding 80 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses above 120 mg and total daily doses above 150 mg has not been systematically evaluated.

Adult patients

Treatment with Atomoxetine® should be initiated at a total daily dose of 40 mg. This dose should be maintained for at least 7 days prior to increasing the dose based on clinical response and tolerability. The maximum recommended daily dose ranges from 80 mg to 100 mg. The maximum recommended total daily dose is 100 mg. The safety of single doses above 120 mg and total daily doses above 150 mg has not been systematically evaluated.

Additional safety information regarding the use of this medicinal product

Pretreatment evaluation

Prior to initiating treatment, a thorough medical history should be obtained and a baseline cardiovascular assessment performed, including measurement of blood pressure (BP) and heart rate (HR) (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

Ongoing monitoring

Regular assessment of cardiovascular function, including measurement of BP and HR, should be performed after each dose adjustment and then every 6 months. For pediatric patients, the use of percentile-based methods for BP assessment is recommended. For adult patients, current hypertension guidelines should be followed (see section "Special precautions for use").

Discontinuation of treatment

No prominent withdrawal symptoms have been reported during clinical studies. In the event of significant adverse effects, atomoxetine administration may be abruptly discontinued or the dose gradually reduced over an appropriate period.

Treatment with Atomoxetine® should not be indefinite. After one year of treatment, the need for continued therapy should be re-evaluated, especially when the patient has achieved sustained satisfactory response.

Special populations

Elderly patients

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

Hepatic impairment

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

Renal impairment

In patients with end-stage renal disease, systemic exposure to atomoxetine was higher than in healthy subjects (by approximately 65%), but when exposure was corrected for mg/kg dose, no difference was observed. Therefore, Atomoxetine® may be administered at standard doses to patients with ADHD who have end-stage renal disease or milder degrees of renal impairment. Atomoxetine may exacerbate hypertension in patients with end-stage renal disease (see section "Pharmacological properties").

Approximately 7% of Caucasian patients have a genotype corresponding to non-functional CYP2D6 enzyme (these individuals are referred to as CYP2D6 poor metabolizers). In patients with this genotype, atomoxetine exposure is several-fold higher than in patients with functional enzyme. Therefore, poor metabolizers are at increased risk of adverse reactions (see sections "Pharmacological properties" and "Adverse reactions"). For patients with known poor metabolizer genotype, consideration may be given to initiating treatment with a lower starting dose and gradual dose titration.

Administration

For oral use. Atomoxetine® may be administered independently of food intake.

Capsules must not be opened, and the contents should not be removed or taken by any other route.

Children

The safety and efficacy of atomoxetine in children and adolescents under 6 years of age have not been established; therefore, Atomoxetine® should not be prescribed to children in this age group (see section "Special precautions for use").

Overdose.

Signs and symptoms

Post-marketing experience has reported non-fatal cases of acute and chronic atomoxetine overdose when used as monotherapy. The most commonly reported symptoms associated with acute and chronic overdose were gastrointestinal disorders, somnolence, dizziness, tremor, and behavioral disturbances. Hyperactivity and agitation have also been reported. Additionally, signs and symptoms consistent with mild to moderate activation of the autonomic nervous system (e.g., tachycardia, increased BP, mydriasis, dry mouth) have been observed. There have also been reports of pruritus and rash. Most cases were mild or moderate in severity. In some cases of atomoxetine-related overdose, epileptiform seizures have been reported, and very rarely, QT interval prolongation and serotonin syndrome. Fatal cases have also been reported following acute overdose involving concomitant intake of atomoxetine and at least one other medicinal product.

Experience with atomoxetine overdose during clinical trials is limited.

Treatment

Ensure adequate pulmonary ventilation. Activated charcoal may be administered within 1 hour of overdose to reduce absorption. Continuous monitoring of cardiac function and vital signs is recommended, along with appropriate symptomatic and supportive measures. The patient should be observed for at least 6 hours. Since atomoxetine is highly protein-bound, dialysis is unlikely to be effective in treating overdose.

Adverse reactions.

Paediatric population

Short description of safety profile

Clinical studies have shown that the most commonly reported adverse reactions with atomoxetine were headache, abdominal pain¹, and decreased appetite, observed in approximately 19%, 18%, and 16% of patients, respectively. These reactions rarely led to treatment discontinuation (discontinuation rates were 0.1% for headache, 0.2% for abdominal pain, and 0% for decreased appetite). Episodes of abdominal pain and decreased appetite were usually transient.

Due to decreased appetite in the early stages of treatment, growth and weight gain were temporarily delayed. On average, after an initial reduction in weight and height growth velocity in patients receiving atomoxetine, growth increased back to the expected population norms predicted by baseline data during long-term treatment.

Nausea, vomiting, and somnolence² may occur in approximately 10–11% of patients, particularly during the first month of therapy. However, these events were generally mild or moderate in severity and transient, and did not lead to treatment discontinuation in a significant number of cases (discontinuation rate ≤ 0.5%).

During placebo-controlled trials involving both children and adults, increases in heart rate, systolic and diastolic blood pressure were observed in patients taking atomoxetine (see section "Special warnings and precautions for use").

Due to the effect on noradrenergic tone, orthostatic hypotension (0.2%) and syncope (0.8%) have been observed in patients receiving atomoxetine. Atomoxetine should be used with caution in patients with conditions predisposing to orthostatic hypotension.

The following adverse reactions are based on reports of adverse events and laboratory test results from clinical trials, as well as spontaneous post-marketing reports in children and adolescents.

Frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Metabolism and nutrition disorders: very common – decreased appetite; common – anorexia (loss of appetite).

Psychiatric disorders: common – irritability, mood swings, insomnia³, agitation*, anxiety, depression and depressed mood*, tics*; uncommon – suicidal behaviour, aggression, hostility, emotional lability*, psychosis (including hallucinations)*; frequency not known – bruxism.

Nervous system disorders: very common – headache, somnolence²; common – dizziness; uncommon – syncope, tremor, migraine, paraesthesia*, hypoaesthesia*, seizures**.

Eye disorders: common – mydriasis; uncommon – blurred vision.

Cardiac disorders: uncommon – palpitations, sinus tachycardia, QT interval prolongation**.

Vascular disorders: rare – Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnoea (see section "Special warnings and precautions for use").

Gastrointestinal disorders: very common – abdominal pain¹, vomiting, nausea; common – constipation, dyspepsia.

Hepatobiliary disorders: uncommon – increased blood bilirubin levels*; rare – abnormal levels/increased liver enzymes, jaundice, hepatitis, hepatic injury, acute liver failure*.

Skin and subcutaneous tissue disorders: common – dermatitis, pruritus, rash; uncommon – hyperhidrosis, allergic reactions.

Renal and urinary disorders: rare – urinary hesitation, urinary retention.

Reproductive system and breast disorders: rare – priapism, genital pain in male patients.

General disorders and administration site conditions: common – fatigue, lethargy, chest pain (see section "Special warnings and precautions for use"); uncommon – asthenia.

Investigations: very common – increased blood pressure⁴, increased heart rate⁴; common – weight decreased.

¹Includes upper abdominal pain, stomach discomfort, abdominal discomfort, and epigastric discomfort.

²Includes sedation.

³Includes difficulty falling asleep, middle-of-the-night insomnia, and early morning awakening.

⁴Heart rate and blood pressure results are based on vital sign measurements.

*See section "Special warnings and precautions for use".

**See sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use".

Poor metabolizers (PM) of CYP2D6:

The adverse reactions listed below were observed in at least 2% of patients who are poor metabolizers (PM) of CYP2D6, and their frequency was statistically significantly higher in PM patients compared to patients who are extensive metabolizers (EM) of CYP2D6: decreased appetite (24.1% PM, 17% EM); insomnia composite (including insomnia, sleep disorders, difficulty falling asleep, 14.9% PM, 9.7% EM); depression composite (including depression, major depressive disorder, depressive symptoms, depressed mood, and dysphoria, 6.5% PM, 4.1% EM), weight loss (7.3% PM, 4.4% EM), constipation (6.8% PM, 4.3% EM), tremor (4.5% PM, 0.9% EM), sedation (3.9% PM, 2.1% EM), rash (3.9% PM, 1.7% EM), enuresis (3% PM, 1.2% EM), conjunctivitis (2.5% PM, 1.2% EM), syncope (2.5% PM, 0.7% EM), early morning awakening (2.3% PM, 0.8% EM), mydriasis (2% PM, 0.6% EM). The following event did not meet the predefined criteria but is noteworthy: generalized anxiety disorder (0.8% PM, 0.1% EM). In addition, in trials lasting up to 10 weeks, weight loss was more pronounced in PM patients (average of 0.6 kg in EM and 1.1 kg in PM).

Adults

Short description of safety profile

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

The following adverse reactions are based on reports of adverse events and laboratory test results from clinical trials, as well as spontaneous post-marketing reports in adults.

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

Metabolism and nutrition disorders: very common – decreased appetite.

Psychiatric disorders: very common – insomnia²; common – agitation*, decreased libido, sleep disorders, depression and depressed mood*, anxiety; uncommon – suicidal behaviour*, aggression, hostility and emotional lability*, restlessness, tics*; rare – psychosis (including hallucinations)*.

Nervous system disorders: very common – headache; common – dizziness, taste disturbance, paraesthesia, somnolence (including sedation), tremor; uncommon – syncope, migraine, hypoaesthesia*; rare – seizures**.

Eye disorders: uncommon – blurred vision.

Cardiac disorders: common – palpitations, tachycardia; uncommon – QT interval prolongation**.

Vascular disorders: common – flushing, hot flushes; uncommon – cold extremities; rare – Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnoea (see section "Special warnings and precautions for use").

Gastrointestinal disorders: very common – dry mouth, nausea; common – abdominal pain¹, constipation, dyspepsia, flatulence, vomiting.

Hepatobiliary disorders: rare – abnormal levels/increased liver enzymes, jaundice, hepatitis, hepatic injury, acute liver failure, increased blood bilirubin levels*.

Skin and subcutaneous tissue disorders: common – dermatitis, hyperhidrosis, rash; uncommon – allergic reactions⁴, pruritus, urticaria.

Musculoskeletal and connective tissue disorders: uncommon – muscle spasms.

Renal and urinary disorders: common – dysuria, pollakiuria, urinary hesitation, urinary retention; uncommon – urinary frequency.

Reproductive system and breast disorders: common – dysmenorrhoea, ejaculation disorder, erectile dysfunction, prostatitis, genital pain in male patients; uncommon – anejaculation, irregular menstrual cycle, orgasmic disorder; rare – priapism.

General disorders and administration site conditions: common – asthenia, fatigue, lethargy, chills, restlessness, irritability, thirst; uncommon – feeling cold, chest pain (see section "Special warnings and precautions for use").

Investigations: very common – increased blood pressure³, increased heart rate³; common – weight decreased.

¹Includes upper abdominal pain, stomach discomfort, abdominal discomfort, and epigastric discomfort.

²Includes difficulty falling asleep, middle-of-the-night insomnia, and early morning awakening.

³Heart rate and blood pressure results are based on vital sign measurements.

⁴Includes anaphylactic reactions and angioedema.

*See section "Special warnings and precautions for use".

**See sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use".

Poor metabolizers (PM) of CYP2D6

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

Shelf life. 3 years.

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

Packaging.

For 10 mg capsules: 7 capsules in a blister; 1 blister in a cardboard box.

For 18 mg, 25 mg, and 40 mg capsules: 7 capsules in a blister; 1 or 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

FARMATEN INTERNATIONAL S.A.

FARMATEN S.A.

Manufacturer's location and address of place of business.

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

Dervenakion 6, Pallini Attica 15351, Greece.