Strattera, Page 3

Strattera® is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). The efficacy of Strattera Capsules was established in seven clinical trials in outpatients with ADHD.


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Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.

6.2 Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval use of STRATTERA. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular system — QT prolongation, syncope.

General disorders and administration site conditions — Lethargy.

Nervous system disorders — Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances.

Seizures — Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre–existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between STRATTERA and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.

Urogenital system — Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.

7 DRUG INTERACTIONS

7.1 Monoamine Oxidase Inhibitors

With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Contraindications (4.2)].

7.2 Effect of CYP2D6 Inhibitors on Atomoxetine

In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady–state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6– to 8–fold and Css,max is about 3– to 4–fold greater than atomoxetine alone.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.

7.3 Pressor Agents

Because of possible effects on blood pressure, STRATTERA should be used cautiously with pressor agents (e.g., dopamine, dobutamine).

7.4 Albuterol

STRATTERA should be administered with caution to patients being treated with systemically–administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status.

7.5 Effect of Atomoxetine on P450 Enzymes

Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

CYP3A Substrate (e.g., Midazolam) — Coadministration of STRATTERA (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A.

CYP2D6 Substrate (e.g., Desipramine) — Coadministration of STRATTERA (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6.

7.6 Alcohol

Consumption of ethanol with STRATTERA did not change the intoxicating effects of ethanol.

7.7 Methylphenidate

Coadministration of methylphenidate with STRATTERA did not increase cardiovascular effects beyond those seen with methylphenidate alone.

7.8 Drugs Highly Bound to Plasma Protein

In vitro drug–displacement studies were conducted with atomoxetine and other highly–bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin.

7.9 Drugs that Affect Gastric pH

Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on STRATTERA bioavailability.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C — Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/kg/day. The 100 mg/kg dose is approximately 23 times the maximum human dose on a mg/m2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the maximum human dose.

Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the maximum human dose on a mg/m2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 of 2 studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the maximum human dose on a mg/m2 basis) but not at 20 mg/kg/day.

No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the maximum human dose on a mg/m2 basis) by gavage throughout the period of organogenesis.

No adequate and well-controlled studies have been conducted in pregnant women. STRATTERA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

8.2 Labor and Delivery

Parturition in rats was not affected by atomoxetine. The effect of STRATTERA on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if STRATTERA is administered to a nursing woman.

8.4 Pediatric Use

Anyone considering the use of STRATTERA in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions (5.1)].

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The safety, efficacy, and pharmacokinetics of STRATTERA in pediatric patients less than 6 years of age have not been evaluated.

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m2 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown.

8.5 Geriatric Use

The safety, efficacy and pharmacokinetics of STRATTERA in geriatric patients have not been evaluated.

8.6 Hepatic Insufficiency

Atomoxetine exposure (AUC) is increased, compared with normal subjects, in EM subjects with moderate (Child–Pugh Class B) (2–fold increase) and severe (Child–Pugh Class C) (4–fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency [see Dosage and Administration (2.3)].

8.7 Renal Insufficiency

EM subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. STRATTERA can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen.

8.8 Gender

Gender did not influence atomoxetine disposition.

8.9 Ethnic Origin

Ethnic origin did not influence atomoxetine disposition (except that PMs are more common in Caucasians).

8.10 Patients with Concomitant Illness

Tics in patients with ADHD and comorbid Tourette’s Disorder — Atomoxetine administered in a flexible dose range of 0.5 to 1.5 mg/kg/day (mean dose of 1.3 mg/kg/day) and placebo were compared in 148 randomized pediatric (age 7-17 years) subjects with a DSM-IV diagnosis of ADHD and comorbid tic disorder in an 18 week, double- blind, placebo-controlled study in which the majority (80%) enrolled in this trial with Tourette’s Disorder (Tourette’s Disorder: 116 subjects; chronic motor tic disorder: 29 subjects). A non-inferiority analysis revealed that STRATTERA did not worsen tics in these patients as determined by the Yale Global Tic Severity Scale Total Score (YGTSS). Out of 148 patients who entered the acute treatment phase, 103 (69.6%) patients discontinued the study. The primary reason for discontinuation in both the atomoxetine (38 of 76 patients, 50.0%) and placebo (45 of 72 patients, 62.5%) treatment groups was identified as lack of efficacy with most of the patients discontinuing at Week 12. This was the first visit where patients with a CGI-S≥4 could also meet the criteria for “clinical non-responder” (CGI-S remained the same or increased from study baseline) and be eligible to enter an open-label extension study with atomoxetine.

Anxiety in patients with ADHD and comorbid Anxiety Disorders — In two post-marketing, double-blind, placebo-controlled trials, it has been demonstrated that treating patients with ADHD and comorbid anxiety disorders with STRATTERA does not worsen their anxiety.

In a 12-week double-blind, placebo-controlled trial, 176 patients, aged 8-17, who met DSM-IV criteria for ADHD and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized. Following a 2-week double-blind placebo lead-in, STRATTERA was initiated at 0.8 mg/kg/day with increase to a target dose of 1.2 mg/kg/day (median dose 1.30 mg/kg/day +/- 0.29 mg/kg/day). STRATTERA did not worsen anxiety in these patients as determined by the Pediatric Anxiety Rating Scale (PARS). Of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) patients discontinued the study.

In a separate 16-week, double-blind, placebo-controlled trial, 442 patients aged 18-65, who met DSM-IV criteria for adult ADHD and social anxiety disorder (23% of whom also had Generalized Anxiety Disorder) were randomized. Following a 2-week double-blind placebo lead-in, STRATTERA was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day +/- 19.5 mg/day). STRATTERA did not worsen anxiety in these patients as determined by the Liebowitz Social Anxiety Scale (LSAS). Of the 436 patients who completed the double-blind placebo lead-in, 172 (39.4%) patients discontinued the study.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

STRATTERA is not a controlled substance.

9.2 Abuse

In a randomized, double–blind, placebo–controlled, abuse–potential study in adults comparing effects of STRATTERA and placebo, STRATTERA was not associated with a pattern of response that suggested stimulant or euphoriant properties.

9.3 Dependence

Clinical study data in over 2000 children, adolescents, and adults with ADHD and over 1200 adults with depression showed only isolated incidents of drug diversion or inappropriate self–administration associated with STRATTERA. There was no evidence of symptom rebound or adverse reactions suggesting a drug–discontinuation or withdrawal syndrome.

Animal Experience — Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine.

10 OVERDOSAGE

10.1 Human Experience

No fatal overdoses occurred in clinical trials. There is limited clinical trial experience with STRATTERA overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of STRATTERA and at least one other drug. There have been no reports of death involving overdose of STRATTERA alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving STRATTERA, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of STRATTERA were somnolence, agitation, hyperactivity, abnormal behavior, and gastrointestinal symptoms. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., mydriasis, tachycardia, dry mouth) have also been observed. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations.

10.2 Management of Overdose

An airway should be established. Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after ingestion. Activated charcoal may be useful in limiting absorption. Because atomoxetine is highly protein–bound, dialysis is not likely to be useful in the treatment of overdose.

11 DESCRIPTION

STRATTERA® (atomoxetine HCl) is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is the R(-) isomer as determined by x–ray diffraction. The chemical designation is (-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. The molecular formula is C17H21NO•HCl, which corresponds to a molecular weight of 291.82. The chemical structure is:

Chemical Structure

Atomoxetine HCl is a white to practically white solid, which has a solubility of 27.8 mg/mL in water.

STRATTERA capsules are intended for oral administration only.

Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, 60, 80, or 100 mg of atomoxetine. The capsules also contain pregelatinized starch and dimethicone. The capsule shells contain gelatin, sodium lauryl sulfate, and other inactive ingredients. The capsule shells also contain one or more of the following:

FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide. The capsules are imprinted with edible black ink.

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