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The physician’s psychoactive medication resource guide
25% of your patients taking an antidepressant will have
weight gain and the weight gain is directly caused by the antidepressant.
How to avoid Strattera withdrawal side effects click here
FDA Talk Paper
December 17, 2004 Media Inquiries: 301-827-6242
Consumer Inquiries: 888-INFO-FDA
New Warning for Strattera
The Food and Drug Administration (FDA) is advising health care professionals about a new warning
for Strattera, a drug approved for attention deficit hyperactivity disorder (ADHD) in adults and
children. The labeling is being updated with a bolded warning about the potential for severe liver
injury following two reports (a teenager and an adult) in patients who had been treated with
Strattera for several months, both of whom recovered.
The labeling warns that severe liver injury may progress to liver failure resulting in death or the
need for a liver transplant in a small percentage of patients. The labeling also notes that the
number of actual cases of severe liver injury is unknown because of under-reporting of post-
marketing adverse events.
The bolded warning indicates that the medication should be discontinued in patients who
developed jaundice (yellowing of the skin or whites of the eyes) or laboratory evidence of liver
Strattera has been on the market since 2002 and has been used in more than 2 million patients. In
clinical trials of 6000 patients, no signal for liver problems (hepatotoxicity) had emerged.
FDA has asked the manufacturer to add a bolded warning about severe liver injury to the labeling.
Eli Lilly has agreed to alert health care professionals about the new information in a Dear Health
Professional letter. The company will also update the patient package insert with information about
the signs and symptoms of liver problems, which include:
◦Pruritus (Itchy skin)
◦Upper right-sided abdominal tenderness
◦Or unexplained “flu-like” symptoms
Health care professionals are encouraged to report any unexpected adverse events associated
with Strattera directly to Eli Lilly, Indianapolis, Ind., at 1800-LillyRx or to the FDA MedWatch
program at 1800-FDA-1088. The MedWatch form is available online at
http://www.fda.gov/medwatch/safety/3500.pdf for download by mail (or fax, 1800-FDA-0178) to
MedWatch, HFD-410, FDA, 5600 Fishers Lane, Rockville, Md. 20857.
Strattera is really an antidepressant that Eli Lilly could not find a market for in the early 1990's. Eli
Lilly sat on the drug until they came up with the idea of using it for ADHD. If you are giving Strattera
to your child or thinking about doing so, know you are really giving them an antidepressant and all
caution should be taken.
Before allowing your child to take Strattera, please read down this page and pay special note to the
bold text. We know most parents would not give their child medication if they knew it would
cause more harm than good. We also understand the need for a parent to receive verifiable
information that is also reliable.
The Strattera information below is from the Physicians' Desk Reference, supplied by Eli Lilly. Their
report, not ours. We are only evaluating their data.
At issue with Strattera as well as with the class of antidepressants called SSRIs, is the metabolism
and side effects.
Eli Lilly Employees - It is time for you to come clean like many of the FDA scientist have done over
the past month. Children are the future of our civilization and you are killing them. You can send me
an e-mail that will be held in confidence if you wish.
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 C
NO•HCl, which corresponds to a molecular weight of 291.82.
Pharmacodynamics and Mechanism of Action
The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is
thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter
depletion studies. (Editors note - Eli Lilly admits upfront this is guess work)
Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism
through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5
hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6
metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak
plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with
normal activity [extensive metabolizers (EMs)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause
similar increases in exposure. (Editors note - If your child is a poor metabolizer, the half life or how long the drug stays in the
system is 10 fold that of normal metabolizer plus the peak concentration of Strattera is 5 fold higher)
The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using
population pharmacokinetic studies. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and
adults. When doses were normalized to a mg/kg basis, similar half-life, C
, and AUC values were observed in children, adolescents, and adults.
Clearance and volume of distribution after adjustment for body weight were also similar.
Absorption and Distribution --Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in
EMs and 94% in PMs. Maximal plasma concentrations (C
) are reached approximately 1 to 2 hours after dosing.
Metabolism and Elimination --Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced
activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs).
For PMs, AUC of atomoxetine is approximately 10-fold and C
is about 5-fold greater than EMs. Laboratory tests are available to
identify CYP2D6 PMs. Coadministration of STRATTERA with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine,
results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary. Atomoxetine did not inhibit
or induce the CYP2D6 pathway. (Editors note - Eli Lilly finally is admitting there is a test that can determine this)
The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is
equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine
concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-
hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and
other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in
plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).
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 C
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). (Editors note - The difference here in half life for poor
metabolizer is 34-40 hours vs. 6-8 hours. We are talking days difference. If you are still taking Strattera on top of this, imagine what
is happening inside the body)
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 feces (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.
CYP2D6 activity and atomoxetine plasma concentration --Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In
EMs, inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage
adjustment of STRATTERA in EMs may be necessary when coadministered with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine. In
vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.
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.
Albuterol --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.
Alcohol --Consumption of ethanol with STRATTERA did not change the intoxicating effects of ethanol.
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.
Methylphenidate --Coadministration of methylphenidate with STRATTERA did not increase cardiovascular effects beyond those seen with
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.
In pediatric placebo-controlled trials, STRATTERA-treated subjects experienced a mean increase in heart rate of about 6 beats/minute compared with
placebo subjects. At the final study visit before drug discontinuation, 3.6% (12/335) of STRATTERA-treated subjects had heart rate increases of at
least 25 beats/minute and a heart rate of at least 110 beats/minute, compared with 0.5% (1/204) of placebo subjects. No pediatric subject had a heart
rate increase of at least 25 beats/minute and a heart rate of at least 110 beats/minute on more than one occasion. Tachycardia was identified as an
adverse event for 1.5% (5/340) of these pediatric subjects compared with 0.5% (1/207) of placebo subjects. The mean heart rate increase in
extensive metabolizer (EM) patients was 6.7 beats/minute, and in poor metabolizer (PM) patients 10.4 beats/minute.
Routine laboratory tests are not required.
CYP2D6 metabolism --Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a
given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs.
Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong
inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA. (Eli Lilly admits a
higher rate of adverse reaction if you are a poor metabolizer)
CYP2D6 inhibitors --Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs, selective inhibitors of CYP2D6
increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage adjustment of STRATTERA may be
necessary when coadministered with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine. In EM individuals treated with paroxetine or
fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and C
is about 3- to 4-fold greater than atomoxetine alone.
Child and Adolescent Clinical Trials
Reasons for discontinuation of treatment due to adverse events in child and adolescent clinical trials --In acute child and adolescent placebo-
controlled trials, 3.5% (15/427) of atomoxetine subjects and 1.4% (4/294) placebo subjects discontinued for adverse events. For all studies, (including
open-label and long-term studies), 5% of extensive metabolizer (EM) patients and 7% of poor metabolizer (PM) patients discontinued
because of an adverse event. Among STRATTERA-treated patients, aggression (0.5%, N=2); irritability (0.5%, N=2); somnolence
(0.5%, N=2); and vomiting (0.5%, N=2) were the reasons for discontinuation reported by more than 1 patient.
The following adverse events occurred in at least 2% of PM patients and were either twice as frequent or statistically significantly more frequent in PM
patients compared with EM patients: decreased appetite (23% of PMs, 16% of EMs); insomnia (13% of PMs, 7% of EMs); sedation (4% of PMs, 2% of
EMs); depression (6% of PMs, 2% of EMs); tremor (4% of PMs, 1% of EMs); early morning awakening (3% of PMs, 1% of EMs); pruritus (2% of PMs,
1% of EMs); mydriasis (2% of PMs, 1% of EMs).
General Dosing Information
STRATTERA may be taken with or without food.
The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated.
Dosing adjustment for hepatically impaired patients --For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is
recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose
(for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal.
Dosing adjustment for use with a strong CYP2D6 inhibitor --In children and adolescents up to 70 kg body weight administered strong CYP2D6
inhibitors, e.g., paroxetine, fluoxetine, and quinidine, STRATTERA should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of
1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.
In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine,
STRATTERA should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and
the initial dose is well tolerated.