Strattera withdrawal. Find how to get
Strattera withdrawal relief as well as Strattera wityhdrawal
side effects. Strattera withdrawal. If you are taking
Strattera as well as an anti-anxiety medication
(benzodiazepine), the anti-anxiety medication must be
discontinued first. If you are only discontinuing the
Strattera the Strattera must be reduced very slowly to
prevent withdrawal side effects from the anti-anxiety drug.
Strattera slows the metabolism rate of anti-anxiety drugs
and when the Strattera is removed from the system the
anti-anxiety medication will not take as long to metabolize
and this creates a withdrawal effect from the anti-anxiety
medication. See chapter 9 on the right side of each page for
anti-anxiety medication procedures.
Strattera Withdrawal
Strattera is usually prescribed for ADD/ADHD but is
really an antidepressant and tapering off Strattera
needs to follow that protocol. Click How to Start
above and follow the antidepressant taper
suggestions.
The web site
you are on now, The Road Back, offers information on
how to get off Strattera, prevent Strattera
withdrawal side effects as well as eliminating
current Strattera side effects.
You will find
on this site the complete book, How to Get Off
Psychoactive Drugs Safely. Since 1999, over
40,000 people have now used this information to get
off their antidepressant or other type of
psychoactive medication.
Withdrawal off
of Strattera does not have to be difficult and
handling current Strattera side effects can be
resolved quickly.
Note: If you are taking Strattera as well as an anti-anxiety medication
(benzodiazepine), the anti-anxiety medication must
be discontinued first. If you are only discontinuing
the Strattera the Strattera must be reduced very
slowly to prevent withdrawal side effects from the
anti-anxiety drug. Strattera slows the metabolism
rate of anti-anxiety drugs and when the Strattera is
removed from the system the anti-anxiety medication
will not take as long to metabolize and this creates
a withdrawal effect from the anti-anxiety
medication. See chapter 9 on the right side of each
page for anti-anxiety medication procedures.
FDA Talk Paper
T04-60
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 injury.
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)
-
Jaundice
-
Dark urine
-
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.
STRATTERA™ (Lilly)
(atomoxetine HCl)
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 C 17 H 21 NO•HCl, which corresponds
to a molecular weight of 291.82.
CLINICAL PHARMACOLOGY
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.
Human Pharmacokinetics
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.
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 max , 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
max ) 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
ss,max is about 5-fold greater than EMs
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.
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 ss,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 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.
Drug-Drug Interactions
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
methylphenidate alone.
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.
Precautions
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.
Laboratory Tests
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
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 ss,max 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.
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