Strattera^® (Capsules) Instructions for Use

ATC Code

N06BA09 (Atomoxetine)

Active Substance

Atomoxetine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Centrally acting sympathomimetic. A drug that improves brain metabolism

Pharmacotherapeutic Group

Centrally acting sympathomimetic agent

Pharmacological Action

Centrally acting sympathomimetic. Atomoxetine is a highly selective and potent inhibitor of presynaptic norepinephrine transporters.

Atomoxetine has minimal affinity for other noradrenergic receptors or other neurotransmitter transporters or receptors.

Atomoxetine is not a psychostimulant and is not an amphetamine derivative.

In clinical studies, no exacerbation of disease symptoms or any adverse events associated with withdrawal syndrome were observed upon drug discontinuation.

Pharmacokinetics

Absorption

After oral administration, Atomoxetine is rapidly and almost completely absorbed, reaching C_max in plasma in approximately 1-2 hours.

Atomoxetine is administered regardless of meals or with food.

Distribution

Atomoxetine is well distributed in the body.

It has high affinity for plasma proteins, primarily albumin.

Metabolism

Atomoxetine undergoes primary metabolism involving the CYP2D6 isoenzyme.

The main oxidized metabolite formed, 4-hydroxyatomoxetine, is rapidly glucuronidated.

4-Hydroxyatomoxetine is pharmacologically equivalent to atomoxetine but circulates in plasma at much lower concentrations.

Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in people with deficient CYP2D6 activity, 4-hydroxyatomoxetine can be formed by some other cytochrome P450 isoenzymes, but more slowly.

Atomoxetine does not inhibit or induce the CYP2D6 cycle.

Excretion

The mean T_1/2 of atomoxetine after oral administration is 3.6 hours in patients with extensive metabolism and 21 hours in patients with poor metabolism.

Atomoxetine is mainly excreted in the urine as 4-hydroxyatomoxetine-O-glucuronide.

Pharmacokinetics in Special Clinical Cases

Pharmacokinetics in children and adolescents are similar to those in adults.

The pharmacokinetics of atomoxetine in children under 6 years of age have not been studied.

Indications

• attention deficit hyperactivity disorder (ADHD) in children 6 years and older, adolescents, and adults.

ICD codes

Dosage Regimen

Capsules

The drug is taken orally regardless of meals or with food, once a day, in the morning.

If adverse events occur when taking the drug once a day, patients can be recommended to take it twice a day, dividing the dose into a morning dose and a dose in the late afternoon or early evening.

Gradual dose reduction is not required when discontinuing the drug.

For children and adolescents weighing less than 70 kg, the recommended initial daily dose is approximately 500 mcg/kg and is increased to a therapeutic daily dose of approximately 1.2 mg/kg no earlier than after 3 days.

If there is no improvement in the patient’s condition, the total daily dose can be increased to a maximum dose of 1.8 mg/kg no earlier than 2-4 weeks after starting the drug.

The recommended maintenance dose is approximately 1.2 mg/kg/day.

The recommended maximum daily dose is 1.8 mg/kg or 120 mg.

In children and adolescents weighing less than 70 kg, the safety of a single dose and total daily dose exceeding 1.8 mg/kg has not been systematically evaluated.

For children and adolescents weighing more than 70 kg and adults, the recommended initial daily dose is 40 mg and is increased to a therapeutic daily dose of about 80 mg no earlier than after 3 days.

If there is no improvement in the patient’s condition, the total daily dose can be increased to a maximum dose of 120 mg no earlier than 2-4 weeks after starting the drug.

The recommended maintenance dose is 80 mg.

The recommended maximum daily dose is 120 mg.

In children and adolescents weighing more than 70 kg, as well as in adults, the safety of a single dose greater than 120 mg and a total daily dose greater than 150 mg has not been systematically evaluated.

In patients with moderate hepatic impairment (Child-Pugh class B), the initial and maintenance therapeutic dose should be reduced to 50% of the usual recommended dose.

In patients with severe hepatic impairment (Child-Pugh class C), the initial and maintenance therapeutic dose should be reduced to 25% of the usual dose.

In patients with severe renal impairment (end-stage chronic renal failure), Atomoxetine is eliminated from the body more slowly than in healthy individuals.

However, no differences were noted with dose adjustment.

Therefore, Strattera^® can be prescribed to patients with ADHD with chronic renal failure, including the end stage, using the usual dosage regimen.

Atomoxetine may cause arterial hypertension in patients with end-stage renal failure.

Capsule Administration Instructions

Strattera^® capsules are not intended to be opened.

Atomoxetine causes eye irritation.

If the capsule contents get into the eyes, the eyes should be rinsed immediately with water and a doctor should be consulted.

Hands and contact surfaces should be washed with water.

Adverse Reactions

Children and Adolescents

Digestive system: very common (>10%) – abdominal pain (18%; including abdominal discomfort, epigastric pain and discomfort, stomach discomfort), decreased appetite (16%), vomiting (11%); common (1-10%) – constipation, dyspepsia, nausea (9%), anorexia. These adverse reactions are temporary and usually do not require drug discontinuation. Due to decreased appetite, some patients experienced weight loss at the beginning of treatment (on average about 0.5 kg), weight loss was greater with higher doses. After the initial weight loss, patients taking Strattera showed a slight increase in body weight during long-term therapy. Growth parameters (weight and height) after two years of treatment were close to normal.

Nausea (9%) and vomiting (11%) are most likely during the first month of treatment, are usually mild to moderate, temporary, and are not a reason for treatment discontinuation in a significant number of cases.

Cardiovascular system: uncommon (0.1-1%) – palpitations, sinus tachycardia.

In placebo-controlled studies in children receiving Strattera, there was a mean increase in heart rate of 6 beats/min, and a mean increase in systolic and diastolic blood pressure of 2 mm Hg compared to placebo.

Patients receiving Atomoxetine experienced orthostatic hypotension (0.2%, n=7) and syncope (0.8%, n=26), due to its effect on noradrenergic tone.

Central nervous system: very common (>10%) – drowsiness (includes sedative effect); common (1-10%) – irritability, mood swings, dizziness; uncommon (0.1-1%) – early morning awakening.

Organ of vision: common (1-10%) – mydriasis.

Dermatological reactions: common (1-10%) – dermatitis, rash; uncommon (0.1-1%) – pruritus.

Other: common (1-10%) – influenza, fatigue, weight loss; uncommon (0.1-1%) – asthenia.

Adverse effects in patients with slow metabolism of CYP2D6 substrates, observed in 2% of cases and at the same time twice as often, as well as statistically significantly more often than in patients with rapid metabolism of CYP2D6 substrates: tremor (4.5% and 0.9% respectively), excoriation (3.9% and 1.7% respectively), syncope (2.5% and 0.7% respectively), conjunctivitis (2.5% and 1.2% respectively), early morning awakening (2.3% and 0.8% respectively), mydriasis (2% and 0.6% respectively).

Adults

In adults, the most frequent adverse effects associated with atomoxetine administration were from the gastrointestinal and urogenital tracts. No serious adverse events were observed during short-term or long-term treatment with atomoxetine.

Digestive system: very common (>10%) – decreased appetite, dry mouth, nausea; common (1-10%) – abdominal pain (including abdominal discomfort, epigastric pain and discomfort, stomach discomfort), constipation, dyspepsia, flatulence.

Central nervous system: very common (>10%) – insomnia (includes difficulty falling asleep and middle-of-the-night sleep disturbances); common (1-10%) – decreased libido, dizziness, poor sleep quality, sinus headache; uncommon (0.1-1%) – early morning awakening; very rare (< 0.01%) – syncope.

Cardiovascular system: common (1-10%) – hot flush, palpitations, tachycardia; uncommon (0.1-1.0%) – cold sensation in lower limbs; very rare (< 0.01%) based on spontaneous (post-marketing) reports – peripheral vascular reactions and/or Raynaud’s phenomenon and risk of recurrence of Raynaud’s phenomenon.

In placebo-controlled studies in adults receiving Strattera, there was a mean increase in heart rate of 6 beats/min, and a mean increase in systolic (about 3 mm Hg) and diastolic (about 1 mm Hg) blood pressure compared to placebo.

Urinary system: common (1-10%) – dysuria, urinary retention.

Reproductive system: common (1-10%) – dysmenorrhea, ejaculation disorder, ejaculation failure, erectile disorder, erectile dysfunction, menstrual disorder, prostatitis; very rare (<0.01%) based on spontaneous (post-marketing) reports – painful or prolonged erection, pain in the external male genitalia.

Skin and subcutaneous tissue: common (1-10%) – dermatitis, hyperhidrosis.

Other: common (1-10%) – fatigue, chills, weight loss.

Contraindications

• angle-closure glaucoma;
• severe heart disease;
• concomitant use with MAO inhibitors;
• hypersensitivity to the drug.

With caution, the drug should be used in patients with arterial hypertension, tachycardia, cardiovascular diseases, severe physical exertion, concomitant use of psychostimulants, family history of sudden cardiac death, cerebrovascular accident, history of seizures, as well as in conditions that may lead to arterial hypotension.

Use in Pregnancy and Lactation

Clinical experience with Strattera during pregnancy is insufficient, so the drug should be prescribed during pregnancy only if the expected therapeutic benefit for the mother significantly outweighs the potential risk to the fetus.

It is not known whether Atomoxetine is excreted in breast milk. Caution is required if the drug is prescribed to a nursing mother.

Use in Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh class B), the initial and maintenance therapeutic dose should be reduced to 50% of the usual recommended dose.

In patients with severe hepatic impairment (Child-Pugh class C), the initial and maintenance therapeutic dose should be reduced to 25% of the usual dose.

Use in Renal Impairment

In patients with severe renal impairment (end-stage chronic renal failure), Atomoxetine is eliminated from the body more slowly than in healthy individuals.

However, no differences were noted with dose adjustment.

Therefore, Strattera^® can be prescribed to patients with ADHD with chronic renal failure, including the end stage, using the usual dosage regimen.

Pediatric Use

In children and adolescents weighing less than 70 kg, the safety of a single dose and total daily dose exceeding 1.8 mg/kg has not been systematically evaluated.

For children and adolescents weighing more than 70 kg, the recommended initial daily dose is 40 mg and is increased to a therapeutic daily dose of about 80 mg no earlier than after 3 days.

If there is no improvement in the patient’s condition, the total daily dose can be increased to a maximum dose of 120 mg no earlier than 2-4 weeks after starting the drug.

In children under 6 years of age, there is insufficient data on the safety and efficacy of atomoxetine.

Geriatric Use

The safety and efficacy of Strattera in elderly patients have not been established.

Special Precautions

The drug should be used with caution in patients with hereditary, congenital, or acquired QT interval prolongation.

ADHD symptoms in the form of impaired attention and hyperactivity (identified in more than one social environment, e.g., both at home and at school) may manifest as lack of concentration, distractibility, excessive impatience, impulsivity, disorganization, restlessness and other similar behavioral disorders. The diagnosis of ADHD must meet the ICD-10 criteria.

During drug administration in clinical studies in children and adolescents, the likelihood of developing suicidal thoughts increased. In 12 clinical studies involving 2200 patients (including 1357 patients receiving Strattera and 851 patients receiving placebo), in the group receiving Strattera, the development of suicidal thoughts was detected in 0.37% of cases (5 out of 1357 patients), while no suicidal thoughts were detected in the placebo group. One suicide attempt was reported during these clinical studies; there were no completed suicides.

In rare cases, patients taking Strattera experienced allergic reactions – rash, angioedema, urticaria.

Atomoxetine should not be prescribed for at least 2 weeks after discontinuing MAO inhibitors. Treatment with MAO inhibitors should not be started within 2 weeks after discontinuing atomoxetine.

Many patients taking Atomoxetine experienced some increase in pulse (on average by <10 beats/min) and/or increase in blood pressure (on average by <5 mm Hg). In most cases, these changes did not have a clinically significant effect. Cases of orthostatic hypotension have also been noted.

Against the background of the use of psychostimulants registered for the treatment of ADHD in the USA in children with severe structural heart disease, an increased risk of sudden cardiac death was identified. Atomoxetine does not belong to the class of psychostimulants, as it has an alternative mechanism of therapeutic action in the treatment of ADHD. Nevertheless, given the common registered indication for use (ADHD), caution should be exercised when using atomoxetine in patients with severe physical exertion, concomitant use of psychostimulants, and a family history of sudden cardiac death. Atomoxetine should not be used in patients with severe structural heart disease.

Rare cases of serious liver damage have been reported during atomoxetine administration (two cases of marked increase in liver enzymes and bilirubin per 2 million patients have been described). In patients with manifestations of jaundice or identified laboratory parameters indicating impaired liver function, treatment with atomoxetine should be discontinued.

In clinical studies in adult patients with ADHD taking Atomoxetine, the number of cases of urinary retention was higher compared to the placebo group. Complaints of urinary retention may potentially be considered as a result of atomoxetine use.

Atomoxetine should be discontinued if seizures develop that cannot be explained by other reasons. Atomoxetine should be used with caution in patients with a history of seizures.

The efficacy of treatment with atomoxetine for more than 18 months and the safety of treatment with it for more than 2 years have not been systematically evaluated.

Aggressive behavior or hostility is often observed in children and adolescents with ADHD. There is no conclusive evidence that Atomoxetine can cause aggressive behavior or hostility. However, in clinical studies, aggressive behavior or hostility were observed more frequently in children and adolescents taking Atomoxetine (without statistically significant differences compared to the placebo group). Patients receiving treatment for ADHD require monitoring for the emergence of aggressive behavior or hostility.

Cases of psychotic and manic symptoms, including hallucinations, delusions, and pathologically elevated mood, have been reported during the use of atomoxetine at therapeutic doses in children and adolescents. If these symptoms occur, it is recommended to assess the degree of their association with atomoxetine use and, if necessary, consider discontinuing the drug.

The following symptoms have been noted during atomoxetine administration: anxiety, agitation, panic attacks, insomnia, irritability, impulsivity, akathisia. Patients taking Atomoxetine require monitoring for the development of these symptoms.

Parents and relatives should carefully monitor the emergence of all the above symptoms and suicidal thoughts in children and adolescents taking Atomoxetine, and immediately report this to the attending physician.

The safety and efficacy of Strattera in elderly patients have not been established.

Use in Pediatrics

In children under 6 years of age, there is insufficient data on the safety and efficacy of atomoxetine.

Effect on Ability to Drive Vehicles and Operate Machinery

Drug administration may be accompanied by drowsiness. In this regard, patients taking Strattera should exercise caution when driving dangerous mechanical vehicles, including cars, until they are sure that Atomoxetine does not cause any impairment.

Overdose

Symptoms: in monotherapy, most often – drowsiness, agitation, hyperactivity, behavioral disturbances, and gastrointestinal symptoms. Most manifestations were mild to moderate in severity. Signs and symptoms of mild to moderate sympathetic nervous system activation were also noted (e.g., mydriasis, tachycardia, dry mouth). All patients experienced regression of these symptoms. In some cases, seizures were noted.

Cases of acute overdose with fatal outcome have been reported when atomoxetine was taken as part of combination therapy (with at least one other drug).

Treatment It is recommended to ensure ventilation, monitor cardiac activity and vital signs, and provide symptomatic and supportive treatment. Gastric lavage may be indicated if a short time has passed since drug intake. Activated charcoal may be useful to limit absorption. Because Atomoxetine has a high affinity for plasma proteins, treatment of overdose by dialysis is likely to be inappropriate.

Drug Interactions

When Strattera is used concomitantly with β₂-adrenergic receptor agonists, an increase in their effect on the cardiovascular system is possible (this combination should be used with caution). In healthy adult volunteers, the effect of the drug salbutamol at a standard inhaled dose of 200 mcg on hemodynamic parameters was insignificant compared to the effect of the same dose of this drug administered intravenously. Concomitant use of atomoxetine at a dose of 80 mg/day for 5 days did not lead to an increase in the mentioned effects of albuterol. Heart rate after multiple inhalations of albuterol at a dose of 800 mcg was characterized by similar values both under monotherapy and in combination with atomoxetine.

Concomitant administration of atomoxetine with drugs that cause QT interval prolongation (antipsychotics, antiarrhythmics, moxifloxacin, erythromycin, tricyclic antidepressants, lithium carbonate), as well as with drugs that cause electrolyte imbalance (diuretics) and CYP2D6 inhibitors, increases the risk of QT interval prolongation.

Atomoxetine does not cause clinically significant inhibition or induction of cytochrome P450 isoenzymes, including CYP1A2, CYP3A, CYP2D6 and CYP2C9. In patients with extensive metabolism of CYP2D6 substrates, CYP2D6 inhibitors increase the steady-state plasma C_ss of atomoxetine to a level similar to that in patients with poor metabolism of CYP2D6 substrates.

Based on in vitro studies, it is assumed that the administration of cytochrome P450 inhibitors to patients with poor metabolism of CYP2D6 substrates does not increase the plasma concentration of atomoxetine. Patients using CYP2D6 inhibitor drugs are recommended to have gradual titration of atomoxetine.

Due to the possible effect on blood pressure, Strattera should be used with caution in combination with drugs that affect blood pressure.

Drugs that increase gastric juice pH (magnesium hydrochloride/aluminum hydroxide, omeprazole) do not affect the bioavailability of atomoxetine.

Drugs that affect norepinephrine secretion should be prescribed concomitantly with atomoxetine with caution due to the possibility of increased or synergistic pharmacological effect.

Atomoxetine does not affect the plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam.

Caution is required when using atomoxetine concomitantly with drugs that lower the seizure threshold (antidepressants, antipsychotics, mefloquine, tramadol).

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature between 15°C (59°F) and 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.