Strattera capsules 10mg, No. 7

Attention deficit hyperactivity disorder (ADHD) in children 6 years of age and older, adolescents and adults.

Inside, regardless of food intake or with meals, 1 time / day, in the morning.

Treatment should be supervised by a physician experienced in ADHD patients.

In the event of adverse events occurring when taking the drug 1 time / day, patients can be recommended to take it 2 times / day, with a division of the dose into the morning dose and the dose late in the afternoon or early evening.

Cancellation of the drug does not require a gradual dose reduction.

For children and adolescents weighing up to 70 kg, the recommended initial daily dose is approximately 500 ?g / kg and is increased to a therapeutic daily dose of approximately 1.2 mg / kg no earlier than 3 days later. 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 up to 70 kg, the safety of a single and total daily dose exceeding 1.8 mg / kg has not been systematically evaluated.

For children and adolescents weighing more than 70 kg, as well as adults, the recommended initial daily dose is 40 mg and is increased to a therapeutic daily dose of about 80 mg no earlier than 3 days later. 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 2Ц4 weeks after starting the drug intake.

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 of more than 120 mg and a total daily dose of more than 150 mg has not been systematically evaluated.

In patients with moderate impairment of liver function (class B on the Child-Pugh scale), the initial and maintenance therapeutic dose should be reduced to 50% of the usual recommended dose. In patients with severely impaired liver function (class C on the Child-Pugh scale), the initial and maintenance therapeutic dose should be reduced to 25% of the usual dose.

In patients with severely impaired renal function (end-stage chronic renal failure), atomoxetine is excreted from the body more slowly than in healthy individuals. However, no differences were noted with dose adjustments. Therefore, Strattera can be administered to ADHD patients with chronic renal failure, including end-stage renal disease, using the usual dosage regimen. Atomoxetine can cause hypertension in patients with end-stage renal disease.

Rules for the use of capsules

Strattera capsules are not intended to be opened. Atomoxetine causes eye irritation. If the contents of the capsule get into the eyes, rinse them immediately with water and consult a doctor. Rinse hands and contact surfaces with water.

in contoured cell packs of 7 or 14 pcs .; in a pack of cardboard 1 or 2 (14 pcs.) packaging.

in contoured cell packs of 7 or 14 pcs .; in a pack of cardboard 1 or 2 (14 pcs.) packaging.

in contoured cell packs of 7 or 14 pcs .; in a pack of cardboard 1 or 2 (14 pcs.) packaging.

in contoured cell packs of 7 or 14 pcs .; in a pack of cardboard 1 or 2 (14 pcs.) packaging.

in contoured cell packs of 7 or 14 pcs .; in a pack of cardboard 1 or 2 (14 pcs.) packaging.

hypersensitivity to the drug;

severe heart damage;

simultaneous use with MAO inhibitors;

angle-closure glaucoma.

The drug should be used with caution in patients with arterial hypertension, tachycardia, cardiovascular diseases, severe physical overload, concomitant use of psychostimulants, sudden cardiac death in a family history, impaired cerebral circulation, a history of seizures, as well as conditions that can cause to arterial hypotension.

pharmachologic effect

Centrally acting sympathomimetic. Atomoxetine is a highly selective 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, when the drug was discontinued, there was no increase in the symptoms of the disease or any adverse events associated with the withdrawal syndrome.

Pharmacokinetics

Suction

After oral administration, atomoxetine is rapidly and almost completely absorbed, reaching Cmax in plasma after about 1-2 hours. Atomoxetine is prescribed regardless of food intake or during meals. Distribution Atomoxetine is well distributed in the body. It has a high affinity for plasma proteins, primarily albumin. Metabolism Atomoxetine undergoes primary metabolism with the participation of the isoenzyme CYP2D6. The main oxidized metabolite formed, 4-hydroxyatomoxetine, is rapidly glucuronized. In terms of pharmacological activity, 4-hydroxyatomoxetine is equivalent to atomoxetine, but circulates in plasma at much lower concentrations. Although 4-hydroxyatomoxetine is primarily formed with the participation of CYP2D6, in people with insufficient CYP2D6 activity 4-hydroxyatomoxetine can be formed by some other cytochrome P450 isoenzymes,but more slowly. Atomoxetine does not inhibit or enhance the CYP2D6 cycle. Withdrawal The average T1 / 2 of atomoxetine after oral administration is 3.6 hours in patients with severe metabolism and 21 hours in patients with reduced metabolism. Atomoxetine is mainly excreted in the urine as 4-hydroxyatomoxetine-O-glucuronide. Pharmacokinetics in special clinical situations Pharmacokinetics in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine in children under 6 years of age has not been studied.Pharmacokinetics in special clinical situations Pharmacokinetics in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine in children under 6 years of age has not been studied.Pharmacokinetics in special clinical situations Pharmacokinetics in children and adolescents are similar to those in adults. The pharmacokinetics of atomoxetine in children under 6 years of age has not been studied.

Side effect

Children and adolescents From the digestive system: very often (> 10%) - abdominal pain (18%; including symptoms of abdominal discomfort, epigastric pain and discomfort, stomach discomfort), loss of appetite (16%), vomiting ( eleven%); often (1-10%) - constipation, dyspepsia, nausea (9%), anorexia. These adverse reactions are temporary and usually do not require discontinuation of the drug. Due to decreased appetite in some patients at the beginning of treatment, there was a decrease in body weight (on average, about 0.5 kg), body weight loss was greater at higher doses. After an initial decrease in body weight in patients taking Strattera, there was a slight increase in body weight with prolonged therapy. Growth indicators (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, usually mild to moderate, are temporary and do not cause treatment withdrawal in a significant number of cases. From the side of the cardiovascular system: sometimes (0.1-1%) - palpitations, sinus tachycardia. In placebo-controlled studies in children treated with Strattera, there was an average increase in heart rate by 6 beats / min, and an average increase in systolic and diastolic pressure by 2 mm Hg. compared to placebo. Patients receiving atomoxetine had orthostatic hypotension (0.2%, n = 7) and syncope (0.8%, n = 26) due to its effect on noradrenergic tone. From the side of the central nervous system: very often (> 10%) - drowsiness (including sedation); often (1-10%) - irritability, mood swings,dizziness; sometimes (0.1-1%) - early morning awakening. From the side of the organ of vision: often (1-10%) - mydriasis. Dermatological reactions: often (1-10%) - dermatitis, rash; sometimes (0.1-1%) - itching. Others: often (1-10%) - flu, fatigue, weight loss; sometimes (0.1-1%) - weakness. Side effects in patients with a slow metabolism of CYP2D6 substrates, observed in 2% of cases and at the same time 2 times more often, and also statistically significantly more often than in patients with a fast metabolism of CYP2D6 substrates: tremor (4.5% and 0.9%, respectively), excoriation ( 3.9% and 1.7%, respectively), fainting (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).often (1-10%) - mydriasis. Dermatological reactions: often (1-10%) - dermatitis, rash; sometimes (0.1-1%) - itching. Others: often (1-10%) - flu, fatigue, weight loss; sometimes (0.1-1%) - weakness. Side effects in patients with a slow metabolism of CYP2D6 substrates, observed in 2% of cases and at the same time 2 times more often, and also statistically significantly more often than in patients with a fast metabolism of CYP2D6 substrates: tremor (4.5% and 0.9%, respectively), excoriation ( 3.9% and 1.7%, respectively), fainting (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).often (1-10%) - mydriasis. Dermatological reactions: often (1-10%) - dermatitis, rash; sometimes (0.1-1%) - itching. Others: often (1-10%) - flu, fatigue, weight loss; sometimes (0.1-1%) - weakness. Side effects in patients with a slow metabolism of CYP2D6 substrates, observed in 2% of cases and at the same time 2 times more often, and also statistically significantly more often than in patients with a fast metabolism of CYP2D6 substrates: tremor (4.5% and 0.9%, respectively), excoriation ( 3.9% and 1.7%, respectively), fainting (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).1-1%) - weakness. Side effects in patients with a slow metabolism of CYP2D6 substrates, observed in 2% of cases and at the same time 2 times more often, and also statistically significantly more often than in patients with a fast metabolism of CYP2D6 substrates: tremor (4.5% and 0.9%, respectively), excoriation ( 3.9% and 1.7%, respectively), fainting (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).1-1%) - weakness. Side effects in patients with a slow metabolism of CYP2D6 substrates, observed in 2% of cases and at the same time 2 times more often, and also statistically significantly more often than in patients with a fast metabolism of CYP2D6 substrates: tremor (4.5% and 0.9%, respectively), excoriation ( 3.9% and 1.7%, respectively), fainting (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).5% and 1.2%, respectively), early morning awakening (2.3% and 0.8%, respectively), mydriasis (2% and 0.6%, respectively).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 side effects associated with taking atomoxetine were from the gastrointestinal tract and the urogenital tract. No serious adverse events were observed during short or long term treatment with atomoxetine. From the digestive system: very often (> 10%) - loss of appetite, dry mouth, nausea; often (1-10%) - abdominal pain (including abdominal discomfort, epigastric pain and discomfort, stomach discomfort), constipation, dyspepsia, flatulence. From the side of the central nervous system: very often (> 10%) - insomnia (includes difficulty falling asleep and sleep disturbances in the middle of the night); often (1-10%) - decreased libido, dizziness, poor sleep quality, sinus headache; sometimes (0.1-1%) - early morning awakening; very rarely (<0.01%) - syncope. On the part of the cardiovascular system:often (1-10%) - hot flashes (blood), palpitations, tachycardia; infrequently (0.1-1.0%) - a feeling of coldness in the lower extremities; very rarely (<0.01%) according to spontaneous (post-marketing messages) - peripheral vascular reactions and / or Raynaud's syndrome and the risk of recurrent Raynaud's syndrome. In placebo-controlled studies in adults who received Strattera, there was an average 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 with placebo. From the urinary system: often (1-10%) - dysuria, urinary retention. On the part of the reproductive system: often (1-10%) - dysmenorrhea, ejaculation disorder, lack of ejaculation, erectile dysfunction, erectile dysfunction, menstrual irregularities, prostatitis; very rare (<0.01%) according to spontaneous (post-marketing) messages - painful or prolonged erection, pain in the external genital area in men. Skin and subcutaneous tissue disorders: often (1-10%) - dermatitis, increased sweating.

Others: often (1-10%) - fatigue, chills, weight loss.

Application during pregnancy and lactation

Clinical experience with the use of Strattera during pregnancy is insufficient, therefore, the drug should be prescribed during pregnancy only if the expected benefit of therapy to the mother significantly outweighs the potential risk to the fetus. It is not known whether atomoxetine is excreted in breast milk. If it is necessary to prescribe the drug to a nursing mother, caution is required.

Application for violations of liver function

In patients with moderate impairment of liver function (class B on the Child-Pugh scale), the initial and maintenance therapeutic dose should be reduced to 50% of the usual recommended dose. In patients with severely impaired liver function (class C on the Child-Pugh scale), the initial and maintenance therapeutic dose should be reduced to 25% of the usual dose.

Application for impaired renal function

In patients with severely impaired renal function (end-stage chronic renal failure), atomoxetine is excreted from the body more slowly than in healthy individuals. However, no differences were noted with dose adjustments. Therefore, StratteraЃ can be administered to ADHD patients with chronic renal failure, including end-stage renal disease, using the usual dosage regimen.

Application in children

In children and adolescents weighing up to 70 kg, the safety of a single 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 3 days later. 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.

Use in elderly patients

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

special instructions

The drug should be used with caution in patients with hereditary, congenital or acquired prolongation of the QT interval. Symptoms of ADHD in the form of impaired attention and hyperactivity (identified in more than one social environment, for example, at home and at school) can manifest as lack of concentration, distraction, excessive impatience, impulsivity, disorganization, restlessness, and other similar behavior disorders. A diagnosis of ADHD must meet the ICD-10 criteria. While taking the drug in clinical studies in children and adolescents, the likelihood of developing suicidal thoughts increased. In 12 clinical studies in 2200 patients (including 1357 patients who received Strattera and 851 patients who received placebo), of which 0 in the Strattera group.In 37% of cases, the development of suicidal thoughts was revealed (5 out of 1357 patients), in the placebo group, suicidal thoughts were not detected. In the course of these clinical studies, one suicide attempt was reported, there were no completed suicides. In rare cases, patients taking Strattera have experienced allergic reactions - rash, angioedema, urticaria. Atomoxetine should not be prescribed for at least 2 weeks after discontinuation of MAO inhibitors. Treatment with MAO inhibitors should not be started within 2 weeks after discontinuation of atomoxetine. In many patients taking atomoxetine, there was a slight increase in heart rate (on average, <10 beats / min) and / or an increase in blood pressure (on average, <5 mm Hg). In most cases, these changes did not have a clinically significant effect. Cases of orthostatic hypotension have also been reported.Against the background of the use of psychostimulants registered for the treatment of ADHD in the United States in children with a gross pathology of the heart that violates its structure, an increased risk of sudden cardiac death was revealed. Atomoxetine does not belong to the class of psychostimulants, because has an alternative mechanism of therapeutic action in the treatment of ADHD. Nevertheless, given the general reported indication for use (ADHD), caution should be exercised when using atomoxetine in patients with severe physical overload, concomitant use of psychostimulants, with a family history of sudden cardiac death. Atomoxetine should not be used in patients with severe heart disease. There have been reports of rare cases of serious liver damage while taking atomoxetine (two cases of a pronounced increase in the level of liver enzymes and bilirubin by 2 mln.patients). In patients with manifestations of jaundice or identified laboratory parameters indicating impaired liver function, treatment with atomoxetine should be canceled. In clinical studies in adult ADHD patients taking atomoxetine, the incidence of urinary retention was higher compared with the placebo group. Complaints of urinary retention can potentially be regarded as a result of the use of atomoxetine. It is necessary to stop taking atomoxetine if convulsive seizures develop that cannot be explained by other reasons. Atomoxetine should be used with caution in patients with a history of seizures. The effectiveness 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 common in children and adolescents with ADHD. There is no conclusive evidence that atomoxetine can cause violent behavior or hostility. However, in clinical studies, aggressive behavior or hostility was observed more often in children and adolescents taking atomoxetine (no statistically significant differences compared with the placebo group). Patients receiving treatment for ADHD need to be monitored for aggressive behavior or hostility. Cases of psychotic and manic symptoms, including hallucinations, delusions and abnormal mood elevation, are known to occur with the use of atomoxetine in therapeutic doses in children and adolescents.If these symptoms occur, it is recommended to assess the degree of their connection with the intake of atomoxetine and, if necessary, consider discontinuing the drug. The following symptoms were noted while taking atomoxetine: anxiety, agitation, panic attacks, insomnia, irritability, impulsivity, akathisia. Patients taking atomoxetine should be monitored for the development of these symptoms. Parents and loved ones should carefully monitor the occurrence of all of the above symptoms and suicidal thoughts in children and adolescents taking atomoxetine, and immediately report this to the attending physician.taking atomoxetine, observation is required regarding the development of these symptoms. Parents and loved ones should carefully monitor the occurrence of all of the above symptoms and suicidal thoughts in children and adolescents taking atomoxetine, and immediately report this to the attending physician.taking atomoxetine, observation is required for the development of these symptoms. Parents and loved ones should carefully monitor the occurrence of all of the above symptoms and suicidal thoughts in children and adolescents taking atomoxetine, and immediately report this to the attending physician.

The safety and effectiveness 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. Effects on the ability to drive vehicles and control mechanisms Taking the drug may be accompanied by drowsiness. In this regard, patients taking Stratter should exercise caution when driving hazardous mechanical means, incl. by car until they are sure that atomoxetine is not causing any abnormalities.

Overdose

Symptoms: With monotherapy, the most common are drowsiness, agitation, hyperactivity, behavioral disturbances, and gastrointestinal symptoms. Most of the manifestations were mild to moderate. Signs and symptoms of mild to moderate sympathetic nervous system activation (eg, mydriasis, tachycardia, dry mouth) have also been reported. All patients showed regression of these symptoms. In some cases, convulsions were noted. Cases of acute overdose with a fatal outcome have been reported when taking atomoxetine as part of a combination therapy (with at least one drug). Treatment: Recommended ventilation, cardiac and vital signs monitoring, and symptomatic and supportive treatment. Gastric lavage may be indicated,if a little time has passed after taking the drug. Activated carbon may be helpful to limit absorption. Because Atomoxetine has a high affinity for plasma proteins, treatment of an overdose by dialysis is likely to be inappropriate.

Drug interactions

With the simultaneous use of Strattera with agonists of ?2-adrenergic receptors, their effect on the cardiovascular system may be enhanced (this combination should be used with caution). In healthy adult volunteers, the effect of salbutamol in a standard inhaled dose of 200 ?g on hemodynamic parameters was insignificant compared to the effect of the indicated dose of this drug when administered intravenously. The simultaneous use of atomoxetine at a dose of 80 mg / day for 5 days did not lead to an increase in the indicated effects of albuterol. HR after repeated inhalations of 800 ?g of albuterol was characterized by similar values ??under conditions of both monotherapy and in combination with the use of atomoxetine. Simultaneous administration of atomoxetine with drugs that cause prolongation of the QT interval (antipsychotics, antiarrhythmics, moxifloxacin, erythromycin,tricyclic antidepressants, lithium carbonate), as well as drugs that cause electrolyte imbalance (diuretics) and CYP2D6 inhibitors, increases the risk of increasing the duration of the QT interval. Atomoxetine does not cause clinically significant inhibition or induction of isoenzymes of the cytochrome P450 system, including CYP1A2, CYP3A, CYP2D6 and CYP2C9. In patients with a pronounced metabolism of CYP2D6 substrates, CYP2D6 inhibitors increase the Css of atomoxetine in blood plasma in an equilibrium state to a level similar to that in patients with a slow metabolism of CYP2D6 substrates. Based on in vitro studies, it is assumed that the administration of cytochrome P450 inhibitors to patients with a slow metabolism of CYP2D6 substrates does not increase the concentration of atomoxetine in the blood plasma. Patients using CYP2D6 inhibitor drugsgradual titration of atomoxetine is recommended. Due to the possible effect on blood pressure, Strattera must be used with caution when combined with drugs that affect blood pressure. Drugs that increase the pH of gastric juice (magnesium hydrochloride / aluminum hydroxide, omeprazole) do not affect the bioavailability of atomoxetine. Drugs that affect the secretion of norepinephrine should be administered with caution simultaneously with atomoxetine because of the possibility of an increase or synergism of the pharmacological effect. Atomoxetine does not affect plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam. Caution is required with the simultaneous use of atomoxetine with drugs that lower the threshold of seizure activity (antidepressants, antipsychotics, mefloquine, tramadol).Due to the possible effect on blood pressure, Strattera must be used with caution when combined with drugs that affect blood pressure. Drugs that increase the pH of gastric juice (magnesium hydrochloride / aluminum hydroxide, omeprazole) do not affect the bioavailability of atomoxetine. Drugs that affect the secretion of norepinephrine should be administered with caution simultaneously with atomoxetine because of the possibility of an increase or synergism of the pharmacological effect. Atomoxetine does not affect plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam. Caution is required with the simultaneous use of atomoxetine with drugs that lower the threshold of seizure activity (antidepressants, antipsychotics, mefloquine, tramadol).Due to the possible effect on blood pressure, Strattera must be used with caution when combined with drugs that affect blood pressure. Drugs that increase the pH of gastric juice (magnesium hydrochloride / aluminum hydroxide, omeprazole) do not affect the bioavailability of atomoxetine. Drugs affecting the secretion of norepinephrine should be administered with caution simultaneously with atomoxetine because of the possibility of an increase or synergism of the pharmacological effect. Atomoxetine does not affect plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam. Caution is required with the simultaneous use of atomoxetine with drugs that lower the threshold of seizure activity (antidepressants, antipsychotics, mefloquine, tramadol).increasing the pH of gastric juice (magnesium hydrochloride / aluminum hydroxide, omeprazole) do not affect the bioavailability of atomoxetine. Drugs that affect the secretion of norepinephrine should be administered with caution at the same time as atomoxetine because of the possibility of an increase or synergism of the pharmacological effect. Atomoxetine does not affect plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam. Caution is required with the simultaneous use of atomoxetine with drugs that lower the threshold of seizure activity (antidepressants, antipsychotics, mefloquine, tramadol).increasing the pH of gastric juice (magnesium hydrochloride / aluminum hydroxide, omeprazole) do not affect the bioavailability of atomoxetine. Drugs that affect the secretion of norepinephrine should be administered with caution simultaneously with atomoxetine because of the possibility of an increase or synergism of the pharmacological effect. Atomoxetine does not affect plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam. Caution is required with the simultaneous use of atomoxetine with drugs that lower the threshold of seizure activity (antidepressants, antipsychotics, mefloquine, tramadol).should be administered with caution at the same time as atomoxetine because of the possibility of amplification or synergism of the pharmacological effect. Atomoxetine does not affect plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam. Caution is required with the simultaneous use of atomoxetine with drugs that lower the threshold of seizure activity (antidepressants, antipsychotics, mefloquine, tramadol).should be administered with caution at the same time as atomoxetine due to the possibility of amplification or synergism of the pharmacological effect. Atomoxetine does not affect plasma albumin binding of warfarin, acetylsalicylic acid, phenytoin and diazepam. Caution is required with the simultaneous use of atomoxetine with drugs that lower the threshold of seizure activity (antidepressants, antipsychotics, mefloquine, tramadol).