Strattera

Strattera Mechanism of Action

atomoxetine

Manufacturer:

Eli Lilly

Distributor:

DKSH
Full Prescribing Info
Action
Pharmacotherapeutic Group: Psychoanaleptics, centrally acting sympathomimetics. ATC Code: N06BA09.
Pharmacology: Pharmacodynamics: Strattera is a treatment for Attention-Deficit/Hyperactivity Disorder (ADHD). ADHD was formerly known as Attention Deficit Disorder (ADD) with or without hyperactivity. Atomoxetine is a relatively potent inhibitor of the presynaptic noradrenaline transporter (Ki 4.5nM), a moderate inhibitor of 5HT uptake (Ki 152nM) and a weak inhibitor of dopamine uptake (Ki 658nM), with minimal affinity for the other noradrenergic receptors. Atomoxetine has moderate affinity for 5HT2 and GABAA receptors but poor affinity for most other receptors. The main hydroxyatomoxetine metabolite is equipotent to the parent compound at the noradrenaline transporter (Ki 3.0nM), and a more potent inhibitor of the 5HT transporter (Ki 43nM) than the parent compound.
A thorough QT/QTc study, conducted in healthy adult CYP2D6 poor metaboliser (PM) subjects dosed up to 60mg of atomoxetine twice daily, demonstrated that at maximum expected concentrations the effect of atomoxetine on QTc interval was not significantly different from placebo. There was a slight increase in QTc interval with increased atomoxetine concentration (see Clinical Trials: Cardiac Electrophysiology as follows, Cardiovascular Effects under Precautions and Interactions).
Clinical Trials: The efficacy of Strattera for the treatment of ADHD in children and adolescents (age 6 to 17 years) meeting the Diagnostic and Statistical Manual 4th edition (DSM-IV) criteria was satisfactorily established in four, short-term (6-9 weeks), randomised, double-blind, placebo-controlled studies; one long-term (9 months), randomised, double-blind, placebo-controlled study; and one long-term (2 years), open-label study. The efficacy of Strattera for the treatment of ADHD in adults (18 years of age and older) meeting DSM-IV criteria and with a childhood history of ADHD was established in two, short-term (10 weeks), randomised, double-blind, placebo-controlled studies; and one, long-term (up to 2 years), open-label study. There are no long term, randomised, double-blind, placebo-controlled studies in adults.
Children and Adolescents: The efficacy of Strattera in the treatment of ADHD was established in four acute, randomised, double-blind, placebo-controlled studies of paediatric patients (ages 6 to 17) who met DSM-IV criteria for ADHD (studies LYAC, LYAT, HFBD, HFBK). Approximately one third of the patients met DSM-IV criteria for inattentive subtype and two thirds met criteria for both inattentive and hyperactive/impulsive subtypes.
Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for Strattera-treated and placebo-treated patients using an intent-to-treat analysis. The primary outcome measure was the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive sub-scales. Each item on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM-IV.
Study LYAC: An 8-week randomised, double-blind, placebo-controlled acute treatment study of children and adolescents aged 8 to 18 (N=297), patients received either a fixed dose of Strattera (0.5 mg/kg/day, 1.2 mg/kg/day or 1.8 mg/kg/day) or placebo. Strattera was administered as a divided dose in the early morning and late afternoon/early evening. Treatment with Strattera showed an overall improvement in the reductions from baseline in mean ADHDRS total score. The average score decreased by 25% on 0.5mg/kg/day, 35% on 1.2 mg/kg/day and 34% on 1.8 mg/kg/day Strattera, compared to 15% with placebo. At the two higher doses, improvements in ADHD symptoms were superior and statistically significant (p<0.001 vs placebo) in Strattera-treated patients compared with placebo-treated patients as measured on the ADHDRS scale. The results of Study LYAC are summarised in Figure 1. (See Figure 1.)

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Study LYAT: A 6-week randomised, double-blind, placebo-controlled acute treatment study of children and adolescents aged 6 to 16 (N=171), patients received either Strattera or placebo. Strattera was administered as a single dose in the early morning and titrated on a weight-adjusted basis according to clinical response. The maximum Strattera dose was 1.5 mg/kg/day. The mean final dose of Strattera was approximately 1.3 mg/kg/day. Treatment with Strattera showed an overall improvement in the reductions from baseline in mean ADHDRS total score. The average score decreased by 34% on Strattera, compared to 13% with placebo (p<0.001 vs placebo). Improvements in ADHD symptoms were superior and statistically significant in Strattera-treated patients compared with placebo-treated patients as measured on the ADHDRS scale beginning at one week and through the end of the study. This study demonstrates that Strattera is effective when administered once daily in the morning. The results of Study LYAT are summarised in Figure 2. (See Figure 2.)

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Studies HFBD and HFBK: In two identical, 9-week, acute, randomised, double-blind, placebo-controlled studies of children aged 7 to 13 (Study HFBD, N=147; Study HFBK, N=144), Strattera or methylphenidate was compared with placebo. Methylphenidate was only used to show that the study design was valid (i.e. by its separation from placebo). These studies were not statistically powered to provide a comparative analysis between Strattera and methylphenidate (patient numbers per treatment Study HFBD, Strattera N=65, methylphenidate N=20, placebo N=62; Study HFBK, Strattera N=64, methylphenidate N=18, placebo N=62). The primary comparison of interest in both studies was Strattera vs placebo. Strattera was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight-adjusted basis according to clinical response. The maximum recommended Strattera dose was 2.0 mg/kg/day. The mean final dose of Strattera for both studies was approximately 1.6 mg/kg/day. Treatment with Strattera showed an overall improvement from baseline in mean ADHDRS total score. The average score decreased by 38% on Strattera, compared to 13% with placebo (p<0.0001 vs placebo) in study HFBD and 38% on Strattera, compared to 16% with placebo (p<0.0003 vs placebo) in study HFBK.
Study LYAF: A two-stage relapse prevention study in children and adolescents who met DSM-IV criteria for ADHD. In this study, patients were treated for 12 weeks with Strattera and responders were randomised to a further 40 weeks of treatment discontinuation phase (N=292 Strattera, N=124 placebo). At endpoint (1 year), Strattera was superior to placebo in maintaining clinical response (refer to Kaplan-Meier plot provided as Figure 3). The relapse rate was 18.7% on Strattera vs 31.4% on placebo (p=0.021 all qualified patients). (See Figure 3.)

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Study LYAB: A multi-centre open label safety and efficacy study in children and adolescents who met DSM-IV criteria for ADHD. In this study patients were treated for 10 weeks with Strattera (study period II) and responders were eligible to enter a long term treatment phase of up to 2 years (study period III) (N=301 completing long term treatment). On average, symptoms of ADHD in Strattera-treated patients decreased by 48.5% as measured by the ADHD rating scale total score for study periods II and III. Strattera was well tolerated in this long-term safety study and adverse events did not increase over time. The adverse event profile for PM patients was similar to that for EM patients with a similar tolerability profile as described in the short-term studies.
Examination of population subsets (gender, age, or prior stimulant treatment) did not reveal any differential responsiveness on the basis of these subgroupings.
Adults: The efficacy of Strattera in the treatment of ADHD was established in two randomised, double-blind, placebo-controlled clinical studies of adult patients, age 18 and older who met DSM-IV criteria for ADHD.
Signs and symptoms of ADHD were evaluated using the investigator administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary efficacy measure was the 18-item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales) evaluated by a comparison of mean change from baseline to endpoint using an intent-to-treat analysis.
Studies LYAA and LYAO: In two identical, 10-week, randomised, double-blind, placebo-controlled acute treatment studies (Study LYAA, N=280; Study LYAO, N=256), patients received either Strattera or placebo. Strattera was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response. The maximum Strattera dose was 120 mg/day. The mean final dose of Strattera for both studies was approximately 95 mg/day. Treatment with Strattera showed an overall improvement from baseline in mean CAARS total score. The average score decreased by 28% on Strattera, compared to 18% with placebo (p<0.001 vs placebo) in study LYAA and 30% on Strattera, compared to 20% with placebo (p<0.001 vs placebo) in study LYAO. In both studies, improvements in ADHD symptoms were superior and statistically significant in Strattera-treated patients compared with placebo-treated patients as measured on the CAARS scale.
Study LYAR: An open-label, multi-centre investigation of the long-term safety and tolerability of Strattera in patients aged 18 years or older who meet the DSM-IV criteria for ADHD. This was an open label extension of the LYAA and LYAO studies. Average symptom severity decreased by 30.6% (p<0.001) as measured by the CAARS investigator rated scale for 18 item total ADHD symptoms. The adverse event profile was similar to that observed in short-term studies with most treatment emergent adverse events reported to be of mild or moderate severity.
Examination of population subsets (gender, age, prior stimulant treatment, or CYP2D6 metabolic status) did not reveal any differential responsiveness on the basis of these subgroupings.
Cardiac Electrophysiology: The effect of atomoxetine on QTc prolongation was evaluated in a randomised, double-blinded, positive-(moxifloxacin 400mg) and placebo-controlled, cross-over study in healthy male CYP2D6 PMs. A total of 120 healthy subjects were administered atomoxetine (20mg and 60mg) twice daily for 7 days. Although a statistically significant increase in QTc was associated with increasing plasma concentrations, atomoxetine was not associated with a clinically significant change in QTc (see Pharmacodynamics as previously mentioned, Cardiovascular Effects under Precautions and Interactions).
Pharmacokinetics: Single-dose and steady-state individual pharmacokinetic data were obtained in children, adolescents and adults. After administration of the same mg/kg dose to children, adolescents and adults, similar half-life, Cmax and AUC values were observed. Clearance and volume of distribution after adjustment for body weight were also similar.
Absorption: Atomoxetine is rapidly and almost completely absorbed after oral dosing reaching mean maximal observed plasma concentration (Cmax) approximately 1 to 2 hours after dosing. The Cmax observed after a single 1 mg/kg dose of atomoxetine is 568 ng/mL (range of 92 to 1544 ng/mL).
Strattera can be administered with or without food. In clinical trials with children and adolescents, administration of Strattera with food resulted in a 9% lower Cmax. Administration of Strattera with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption resulting in a 37% lower Cmax. After a high-fat meal, the Tmax was approximately 4 hours after dosing (range of 0.5-16 hours for high-fat; 0.5-6 hours for fasting).
Following oral administration of Strattera, a lower absolute bioavailability (63%) after modest first pass metabolism was observed in extensive CYP2D6 metabolisers, while a higher absolute bioavailability (94%) was observed in poor CYP2D6 metabolisers.
Distribution: The steady-state volume of distribution after intravenous administration was approximately 0.85 L/kg indicating atomoxetine distributes primarily into total body water. In children and adolescents, volume of distribution increased nearly proportionally to increases in body weight. Volume of distribution was similar across the patient weight range after normalising for body weight.
At therapeutic concentrations, 98.5% of atomoxetine in plasma is bound to protein, primarily albumin.
Metabolism: Atomoxetine undergoes biotransformation primarily through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway. There are two major phenotypes associated with CYP2D6: extensive metabolisers (EMs) (93% of Caucasians and 98% of African Americans) and PMs (7% of Caucasians and 2% of African Americans). The major oxidative metabolite formed, regardless of CY2D6 status, is 4-hydroxyatomoxetine, which is rapidly glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine at inhibiting noradrenaline uptake and is slightly more potent at inhibiting 5HT uptake than the parent compound (see Pharmacology under Actions). This metabolite circulates in plasma at much lower concentrations but it is also less plasma protein bound (66%) than the parent compound (98.5%), so that in EMs the exposure to unbound 4-hydroxyatomoxetine exceeds exposure to unbound atomoxetine. Although 4-hydroxyatomoxetine is primarily formed by CYP2D6, in individuals that lack CYP2D6 activity, 4-hydroxyatomoxetine can be formed by several other cytochrome P450 enzymes, but at a slower rate. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has a much less pharmacological activity than atomoxetine and plasma concentrations are lower (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).
People with reduced activity in the CYP2D6 pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine and quinidine also cause increases in exposure. Atomoxetine does not inhibit or induce the CYP2D6 pathway.
Co-administration of Strattera with known inhibitors of CYP2D6 does not result in an increased sensitivity to Strattera, although it may result in higher atomoxetine plasma exposure.
Adjustment of dosing regimens based on metabolism through the CYP2D6 pathway is not necessary.
Elimination: The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in EMs and 21 hours in PMs. Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine.
Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).
Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the faeces (less than 17% of the dose). Only a small fraction of the Strattera dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation.
Hepatic Impairment: Single doses of Strattera were administered to subjects with moderate to severe hepatic impairment (Child-Pugh Class B and C) resulting in reduced atomoxetine clearance, increased atomoxetine exposure (AUC) (2-fold increase for Child-Pugh Class B and 4-fold increase for Child-Pugh Class C) and prolonged half-life of parent drug compared with healthy subjects. However, the maximum exposure observed in subjects with hepatic impairment did not exceed that observed in the population of healthy CYP2D6 PMs. Dosage adjustment is recommended for patients with moderate or severe hepatic impairment (see Hepatic Impairment Dosage Adjustment under Dosage & Administration).
Renal Impairment: Single doses of Strattera were administered to subjects with end stage renal disease, resulting in higher atomoxetine exposure (AUC) than in healthy subjects (about a 65% increase). However, the maximum exposure observed in subjects with end stage renal disease did not exceed that observed in the population of healthy CYP2D6 PMs. Strattera may exacerbate hypertension in patients with end stage renal disease. For those ADHD patients who have end stage renal disease, cautious titration of Strattera to the desired clinical response is recommended, with particular attention to those with hypertension who may experience deterioration in the control of their blood pressure.
Elderly: The pharmacokinetics of atomoxetine have not been evaluated in the elderly population (over 65).
Children and Adolescents: The pharmacokinetics 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.
Gender: Gender did not influence atomoxetine disposition.
Ethnic origin: Ethnic origin did not influence atomoxetine disposition (except that PMs are more common in Caucasians than in African Americans).
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