Pharmacological effect of Strattera
Sympathomimetic central action. Strattera Atomoksetin is a highly selective potent inhibitor of presynaptic norepinephrine transporters. Atomoksetin has minimal affinity for other noradrenergic receptors or to other carriers or receptors of neurotransmitters.
Atomoksetin is not a stimulant and is a derivative of amphetamine. In clinical studies, to remove the drug were observed amplification of symptoms or any adverse effects associated with withdrawal syndrome.
Pharmacokinetics Strattera
Suction
After ingestion atomoksetin rapidly and almost completely absorbed, reaching a Cmax in the plasma after about 1-2 hours Atomoksetin appointed regardless of meals or during meals.
Distribution
Atomoksetin well distributed in the body. Has a high affinity for plasma proteins, primarily – to albumin.
Metabolism
Atomoksetin undergoes primary metabolism involving isoenzyme CYP2D6. Mainly formed oxidized metabolite 4-gidroksiatomoksetin quickly glyukuroniziruetsya. According to the pharmacological activity of 4-gidroksiatomoksetin equivalent atomoksetinu, but circulates in plasma in much lower concentrations.
Although 4-gidroksiatomoksetin initially formed with the participation of CYP2D6, for people with poor CYP2D6 activity 4 gidroksiatomoksetin may form some of the other isozymes of cytochrome P450, but more slowly.
Atomoksetin does not inhibit or induce a cycle CYP2D6.
Breeding
The average T1 / 2 atomoksetina after oral administration is 3.6 hours in patients with severe metabolizers and 21 hours in patients with decreased metabolism. Atomoksetin mainly excreted in the urine as 4-gidroksiatomoksetin-O-glucuronide.
Pharmacokinetics in special clinical situations
Pharmacokinetics in children and adolescents is similar to the pharmacokinetics in adults. Pharmacokinetics atomoksetina in children under 6 years of age has not been studied.
Indications Strattera
- Attention Deficit Hyperactivity Disorder (ADHD) in children 6 years of age or older, teens and adults.
Dosage Strattera
Treatment should be under the supervision of a physician who has experience working with patients with attention deficit hyperactivity disorder.
The drug is taken orally, regardless of the meal or during a meal, as a single daily dose in the morning. In case of adverse events while taking the drug 1 time per day can be recommended for patients taking 2 times a day, dividing the dose by levee and reception late afternoon or early evening.
Canceling the drug does not require a gradual reduction of dose.
Children and adolescents weighing 70 kg the recommended initial daily dose is about 0.5 mg / kg and increased to a therapeutic daily dose of about 1.2 mg / kg no sooner than 3 days. In the absence of improvement of the patient’s total daily dose may be increased to a maximum dose of 1.8 mg / kg no sooner than 2-4 weeks after beginning treatment.
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 70 kg safety of single and total daily doses greater than 1.8 mg / kg, not systematically evaluated.
Children and adolescents weighing over 70 kg and Adults The recommended initial daily dose is 40 mg and increased to a therapeutic daily dose of 80 mg is not earlier than 3 days. In the absence of improvement of the patient’s total daily dose may be increased to a maximum dose of 120 mg is not earlier than 2-4 weeks after beginning treatment.
The recommended maintenance dose is 80 mg. The recommended maximum daily dose is 120 mg.
In children and adolescents with a mass exceeding 70 kg and adults safe single dose of 120 mg and total daily dose of 150 mg are not systematically evaluated.
In patients with moderate hepatic impairment (class of B Child-Pugh), primary and supportive therapeutic dose should be reduced to 50% of the usual recommended dose. In patients with severely impaired liver function (class C Child-Pugh), primary and supportive therapeutic dose should be reduced to 25% of normal dose.
In patients with severely impaired renal function (end-stage renal disease), atomoksetin excreted more slowly than in healthy individuals. However, the dose adjustment of differences were noted. Therefore, the drug can be prescribed Strattera ADHD patients with chronic renal failure, including the terminal stage, applying the usual dosage regimen.
Regulation of capsule
Capsules of the drug Strattera is not intended for dissection. Atomoksetin cause eye irritation. In case of contact with the contents of a capsule in eyes, immediately rinse eyes with water and consult a doctor. Hands and contact surfaces should be washed with water.
Side effects of Strattera
Children and Teens
From the digestive system: Very common (> 10%) – abdominal pain (18%), anorexia (16%), vomiting (11%), often (1-10%) – constipation, indigestion, nausea (9% ), anorexia. These side effects are temporary and usually do not require discontinuation of therapy. Due to reduced appetite, some patients lost weight at the beginning of treatment (on average about 0.5 kg), and weight loss was greater at higher doses. After initial weight loss in patients taking Strattera, noted a slight increase in weight during prolonged therapy. Growth (weight and height) after two years of treatment was close to normal.
Nausea and vomiting are most likely to occur within the first month of treatment, usually mild to moderate severity, are temporary in nature and did not cause discontinuation of treatment in a significant number of cases.
With the cardiovascular system: sometimes (0.1-1%) – the feeling of palpitations, sinus tachycardia.
In placebo-controlled studies in children treated with Strattera, noted an average increase in heart rate by 6 bpm, and the average increase in systolic and diastolic blood pressure – 2 mm Hg compared with placebo.
Patients treated atomoksetin, marked orthostatic hypotension (0.2%) and syncope (0.8%), due to the influence of the drug on noradrenergic tone.
CNS: Frequently (1-10%) – an early morning awakening, irritability, mood swings, dizziness and drowsiness.
On the part of the vision: common (1-10%) – mydriasis.
Dermatological reactions: frequently (1-10%) – dermatitis, itching, rash.
Other: often (1-10%) – flu, fatigue and weight loss.
Side effects in patients with poor metabolism of CYP2D6, were observed in 2% and 2 times more, or significantly more often than patients with a pronounced metabolism of CYP2D6: decreased appetite (24.1% and 17.0% respectively), insomnia (10.5% and 6.8% respectively), the violation of sleep quality (3.8% and 1.5% respectively), enuresis (3% and 1.2% respectively), low mood (3% and 1.0% respectively), tremor (5.1% and 1.1% respectively), early morning awakening ( 3% and 1.1% respectively), conjunctivitis (3% and 1.5% respectively), syncope (2.1% and 0.7% respectively), mydriasis (2.5% and 0.7% respectively).
Adults
In adults, the most frequent side effects associated with taking atomoksetina were part of the gastrointestinal and urogenital tract. Serious adverse events during short-or long-term treatment atomoksetinom not observed.
From the digestive system: Very common (> 10%) – decreased appetite, dry mouth, nausea, frequent (1-10%) – abdominal pain, constipation, dyspepsia, flatulence.
CNS: very common (> 10%) – insomnia, often (1-10%) – an early morning awakening, decreased libido, insomnia, dizziness, impaired sleep quality, sine headache, drowsiness.
With the cardiovascular system: often (1-10%) – Tides (blood), a sense of palpitations, tachycardia, and sometimes (0.1-1.0%) – the feeling of coldness in the lower extremities, very rare ( In placebo-controlled studies in adults treated with Strattera, noted an average increase in heart rate by 6 bpm, and the average increase in systolic (about 3 mm Hg) and diastolic (about 1 mm Hg) blood pressure compared with placebo.
With the urinary system: common (1-10%) – difficulty urinating, urinary retention.
From the reproductive system: often (1-10%) – dysmenorrhea, a violation of ejaculation, lack of ejaculation, erectile dysfunction, erectile dysfunction, menstrual disorders, impaired orgasm, prostate, very rare ( Dermatological reactions: frequently (1-10%) – dermatitis, excessive sweating.
Other: often (1-10%) – weakness, fever, weight loss.
Contraindications Strattera
- Simultaneous use of MAO inhibitors;
- Angle-closure glaucoma;
- Hypersensitivity to the drug.
Caution should be used on patients with hypertension, tachycardia, cardiovascular disease or stroke, as well as for conditions that can lead to arterial hypotension.
Application of pregnancy and breastfeeding
Clinical experience with Strattera during pregnancy is inadequate, and the drug should be prescribed during pregnancy only if the expected benefits of therapy for mother greatly exceeds the potential risk to the fetus.
It is not known whether to select a atomoksetin in breast milk. If necessary, use drugs nursing mothers need to be careful.
Use in hepatic dysfunction
In patients with moderate hepatic impairment (class of Child-Pugh), primary and supportive therapeutic dose should be reduced to 50% of the usual recommended dose. In patients with severely impaired liver function (class C Child-Pugh), primary and supportive therapeutic dose should be reduced to 25% of normal dose.
Use in renal impairment
In patients with severely impaired renal function (end-stage renal disease), atomoksetin excreted more slowly than in healthy individuals. However, the dose adjustment of differences were noted. Therefore, the drug can be prescribed Strattera ADHD patients with chronic renal failure, including the terminal stage, applying the usual dosage regimen.
Cautions
Caution should be used Strattera in patients with hypertension, tachycardia, cardiovascular diseases, cerebrovascular accident, as well as any condition which may lead to hypotension, since Cases of orthostatic hypotension.
Atomoksetin can cause hypertension in patients with end-stage renal disease.
ADHD symptoms as impaired attention and hyperactivity disorder (identified in more than one social environment, for example, both at home and at school) can manifest as lack of concentration, distractibility, excessive restlessness, impulsiveness, disorganization, restlessness, and other similar conduct disorder. The diagnosis of ADHD must meet the criteria of ICD-10.
While taking the drug in clinical trials in children and adolescents increases the risk of suicidal thoughts. In 12 clinical trials in 2,200 patients (including 1,357 patients receiving Strattera and 851 patients receiving placebo) of them in the group treated with Strattera in 0.37% cases were detected the development of suicidal thoughts (5 of 1357 patients) in the placebo group suicidal ideation were not identified. During these clinical trials reported a suicide attempt, completed suicide was not.
In rare cases, patients taking Strattera, there were allergic reactions – rashes, angioedema, urticaria.
Atomoksetin should not be prescribed for at least 2 weeks after discontinuation of MAO inhibitors. Treatment of MAO inhibitors should not begin within 2 weeks after discontinuation atomoksetina.
Many patients taking atomoksetin noted a slight increase in heart rate (an average of Reported rare cases of serious liver injury in patients receiving atomoksetina (described two cases of severe elevation of liver enzymes and bilirubin in the 2 million patients). Patients with signs of jaundice or laboratory parameters identified, indicative of abnormal liver function, treatment Strattera should be abolished.
In clinical studies in adult ADHD patients taking Strattera, the incidence of urinary retention was higher compared with the placebo group. Complaints of urinary retention could potentially be considered as the result of Strattera.
Effectiveness of treatment atomoksetinom more than 18 months and safety of treatment of more than 2 years have not been evaluated systematically.
Aggressive behavior or hostility is often observed in children and adolescents with ADHD. Irrefutable evidence that Strattera can cause aggressive behavior or hostility does not exist. However, in clinical trials, aggressive behavior or hostility were observed more frequently in children and adolescents taking Strattera (no statistically significant differences compared with the placebo group). Patients receiving treatment for ADHD should be monitored for the onset of aggressive behavior or hostility.
The following symptoms were noted in patients receiving Strattera: anxiety, agitation, panic attacks, insomnia, irritability, impulsivity, akathisia, hypomania and mania. Patients taking Strattera, should be monitored for the appearance of these symptoms.
Parents and relatives should carefully monitor the occurrence of all of the above symptoms and suicidal thoughts in children and adolescents taking Strattera, and immediately notify the attending doctor.
Safety and efficacy of Strattera in elderly patients have not been established.
Use in pediatrics
Children under the age of 6 years the safety and effectiveness have not been evaluated.
Effects on ability to drive vehicles and management mechanisms
The drug may be associated with sleepiness. In this regard, patients taking Strattera, you should exercise caution in the management of hazardous mechanical means, including car, as long as they are confident that atomoksetin not cause any disturbances.
Overdose Strattera
Symptoms: monotherapy the most commonly – drowsiness, agitation, hyperactivity, behavioral disorders and disorders of the gastrointestinal tract. Most of the manifestations were mild to moderate severity. Also showed signs and symptoms of sympathetic nervous system activation mild to moderate (eg, mydriasis, tachycardia, dry mouth). All patients had regression of these symptoms. In some cases, there were seizures.
Reported cases of acute overdose with fatal consequences when taking atomoksetina of combination therapy (with at least one drug).
Treatment: It is recommended to provide ventilation, monitor heart activity and key indicators of life, as well as symptomatic and supportive treatment. Can be shown to gastric lavage, if passed not long after taking the drug. It may be useful charcoal to limit absorption. Because atomoksetin has a high affinity to plasma proteins, the treatment of overdose by dialysis rather be impractical.
Drug Interactions Strattera
With the simultaneous application of Strattera with β2-agonists of adrenergic receptors may increase their effects on the cardiovascular system (this combination be used with caution).
Atomoksetin does not cause clinically significant inhibition or induction of cytochrome P450 isoenzymes, including SYP1A2, CYP3A, CYP2D6 and CYP2C9. In patients with severe CYP2D6 metabolism of CYP2D6 inhibitors increase the content of atomoksetina in plasma at steady state to a level similar to that in patients with decreased metabolism of CYP2D6.
Based on in vitro studies it is assumed that the appointment of inhibitors of cytochrome P450 in patients with decreased CYP2D6 metabolism does not increase the concentration of atomoksetina in blood plasma. Patients treated with drugs inhibitors CYP2D6, recommended a gradual titration atomoksetina.
Because of the possible effects on blood pressure Strattera should be used with caution in combination with drugs that affect blood pressure.
Preparations containing magnesium hydrochloride / aluminum hydroxide, omeprazole did not affect the bioavailability atomoksetina.
Agents acting on the secretion of norepinephrine, should be prescribed with care in conjunction with atomoksetinom of the possibility of enhancing or synergistic pharmacological effect.
Atomoksetin not affect the binding to plasma albumin, warfarin, acetylsalicylic acid, phenytoin and diazepam.
