Approved Drug Label (PDF)
Boxed Warning
Additions and/or
revisions underlined:
WARNING: ABUSE,
MISUSE, AND ADDICTION
ADDERALL XR has a
high potential for abuse and misuse, which can lead to the development of a
substance use disorder, including addiction. Misuse and abuse of CNS
stimulants, including ADDERALL XR, can result in overdose and death [see Overdosage (10)], and this risk is
increased with higher doses or unapproved methods of administration, such as
snorting or injection.
Before prescribing
ADDERALL XR, assess each patient’s risk for abuse, misuse, and addiction.
Educate patients and their families about these risks, proper storage of the
drug, and proper disposal of any unused drug. Throughout ADDERALL XR treatment,
reassess each patient’s risk of abuse, misuse, and addiction and frequently
monitor for signs and symptoms of abuse, misuse, and addiction [see Warnings and Precautions (5.1), Drug
Abuse and Dependence (9.2)].
5
Warnings and Precautions
5.1 Abuse, Misuse, and Addiction
Additions and/or
revisions underlined:
ADDERALL XR has a high potential for abuse and
misuse. The use of ADDERALL XR exposes individuals to the risks of abuse and
misuse, which can lead to the development of a substance use disorder,
including addiction. ADDERALL XR can be diverted for non-medical use into
illicit channels
or distribution
[see Drug Abuse and Dependence (9.2)]. Misuse and abuse of CNS stimulants, including ADDERALL XR, can result in overdose and
death [see Overdosage (10)], and this risk is increased with
higher doses or unapproved methods of administration, such as snorting or
injection.
Before prescribing ADDERALL
XR, assess each patient’s risk for abuse, misuse, and addiction. Educate
patients and their families about these risks and proper disposal of any unused
drug. Advise patients to store ADDERALL XR in a safe place, preferably locked,
and instruct patients to not give ADDERALL XR to anyone else. Throughout
ADDERALL XR treatment, reassess each patient’s risk of abuse, misuse, and
addiction and frequently monitor for signs and symptoms of abuse,
misuse, and addiction.
5.9 Motor and Verbal Tics, and Worsening of Tourette’s Syndrome
Additions and/or revisions underlined:
CNS stimulants, including
amphetamine, have been associated with
the onset or exacerbation of motor and verbal tics. Worsening
of Tourette’s syndrome has also been reported [see Adverse Reactions
(6.2)].
Before initiating
ADDERALL XR, assess the family history and clinically evaluate patients for tics or Tourette’s syndrome.
Regularly monitor ADDERALL XR-treated patients for the emergence or worsening of
tics or Tourette’s syndrome, and discontinue treatment if clinically
appropriate.
6
Adverse Reactions
Additions and/or
revisions underlined:
The following adverse reactions are discussed in
greater detail in other sections of the labeling:
Abuse, Misuse, and
Addiction [see Boxed Warning, Warnings and Precautions (5.1), Drug Abuse and
Dependence (9.2, 9.3)]
Risks to Patients with
Serious Cardiac Disease [see Warnings and Precautions (5.2)]
Increased Blood Pressure
and Heart Rate [see Warnings and Precautions (5.3)]
Psychiatric Adverse
Reactions [see Warnings and Precautions (5.4)]
Long-Term Suppression of
Growth in Pediatric Patients [see Warnings and Precautions (5.5)]
Seizures [see Warnings
and Precautions (5.6)]
Peripheral Vasculopathy,
including Raynaud’s Phenomenon [see Warnings and Precautions (5.7)]
Serotonin Syndrome [see
Warnings and Precautions (5.8)]
Motor and Verbal Tics, and
Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.9)]
6.2 Adverse
Reactions Associated with the Use of Amphetamine, ADDERALL XR, or Adderall
Additions and/or revisions underlined:
…
Central Nervous System: Psychotic
episodes at recommended doses, overstimulation, restlessness, irritability,
euphoria, dyskinesia, dysphoria, depression, tremor, motor and verbal
tics, aggression, anger, logorrhea, dermatillomania, paresthesia (including
formication), and bruxism.
…
7
Drug Interactions
7.2 Drug-Laboratory Test Interactions
New subsection added:
Amphetamines
can cause a significant elevation in plasma corticosteroid levels. This
increase is greatest in the evening. Amphetamines may interfere with urinary steroid
determinations.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING
INFORMATION
Additions
and/or revisions underlined:
…
Abuse,
Misuse, and Addiction
Educate patients and
their families about the risks of abuse, misuse, and addiction of ADDERALL
XR, which can lead to overdose and death, and proper disposal of any
unused drug [see Warnings and Precautions (5.1), Drug Abuse and
Dependence (9 .2), Overdosage
(10)]. Advise patients to
store ADDERALL XR in a safe place, preferably locked, and instruct patients to
not give ADDERALL XR to anyone else.
…
Increased
Blood Pressure and Heart Rate
Advise
patients that ADDERALL XR can cause elevations in blood pressure and heart rate
[see Warnings and Precautions (5.3)].
…
Motor
and Verbal Tics, and Worsening of Tourette’s Syndrome
Advise
patients that motor and verbal tics and worsening of Tourette’s syndrome may
occur during
treatment with ADDERALL XR. Instruct patients to notify their healthcare
provider if emergence of new tics or worsening of tics or Tourette’s syndrome
occurs [see Warnings and Precautions
(5.9)].
…
MEDICATION GUIDE
Medication Guide has undergone extensive changes;
please refer to label.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Potential for Abuse and Dependence
(Newly Added
Subsection)
CNS
stimulants, including ADDERALL
XR, other amphetamine-containing products, and methylphenidate,
have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing, and monitor
for signs of abuse and dependence while on therapy.
6
Adverse Reactions
6.2 Adverse Reactions Associated with the Use of Amphetamine, ADDERALL XR, or ADDERALL
(Additions and/or revisions
are underlined)
The
following adverse reactions have been identified during post-approval use of amphetamine, ADDERALL XR, or ADDERALL.
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.
8
Use in Specific Populations
8.1 Pregnancy
(Pregnancy and Lactation Labeling Rule (PLLR)
Conversion; Extensive revisions – please refer to labeling)
8.2 Lactation
(Pregnancy and Lactation Labeling Rule (PLLR)
Conversion; Additions and/or revisions
are underlined)
Risk Summary
Based on limited
case reports in published
literature, amphetamine (d- or
d, l-) is present in human milk, at relative infant
doses of 2% to 13.8% of the maternal
weight-adjusted dosage and a milk/plasma ratio ranging between 1.9 and 7.5. There are no reports
of adverse effects on the breastfed
infant. Long-term neurodevelopmental effects on infants
from amphetamine exposure are unknown. It is possible that large dosages of amphetamine might interfere with milk production, especially in women whose lactation
is not well established. Because of the potential for serious
adverse reactions in nursing infants,
advise patients that breastfeeding is not recommended during
treatment with ADDERALL
XR.
8.4 Pediatric Use
(Additions and/or revisions
are underlined)
ADDERALL XR is indicated for use in children 6 years of age and older.
The safety and efficacy of ADDERALL
XR in children under 6 years
of age have
not
been
studied. Long- term
effects
of amphetamines in children have not been well established.
Long-Term Growth
Suppression
Growth should be monitored
during treatment with stimulants, including ADDERALL XR, and pediatric patients aged 6 to 17 years who are not growing
or gaining weight as expected
may need to have their treatment .
Juvenile Animal
Toxicity Data
Juvenile rats treated with mixed amphetamine salts early in the postnatal period through
sexual maturation demonstrated transient
changes in motor activity. Learning and memory was impaired
at approximately 6 times the maximum recommended human dose (MRHD) given to children on a mg/m^2 basis. No recovery was seen following a drug free period.
A delay in sexual
maturation was observed
at a dose approximately 6 times the MRHD given to children
on a mg/m^2 basis, although
there was no effect on fertility.
In a juvenile developmental study,
rats received daily
oral doses of amphetamine (d to
l
enantiomer ratio of 3:1) of 2, 6, or 20 mg/kg on days 7-13 of age; from day 14 to approximately day 60 of age these doses were given b.i.d. for total daily doses of 4, 12, or 40 mg/kg. The latter doses are approximately 0.6, 2, and 6 times the MRHD
of 30 mg/day, given to children on a mg/m2 basis.
Post dosing hyperactivity was seen at all doses;
motor activity measured
prior to the daily dose was decreased during
the dosing period
but the decreased
motor activity was largely
absent after an 18 day drug-free recovery
period. Performance in the Morris water maze test for learning
and memory was impaired
at the 40 mg/kg dose, and sporadically at the lower doses,
when measured prior to the daily dose during
the treatment period;
no recovery was seen after a 19 day drug-free period. A delay
in the developmental milestones of vaginal opening and preputial separation was seen at 40 mg/kg but there was no effect on fertility.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Additions and/or revisions
are underlined)
Pregnancy Registry
Advise patients that there is a pregnancy exposure
registry that monitors
pregnancy outcomes
in women exposed to ADDERALL
XR during pregnancy.
Pregnancy
Advise patients to notify their healthcare provider if they become pregnant or intend
to become pregnant during treatment with
ADDERALL XR. Advise patients
of the potential fetal effects
from the use of ADDERALL XR during pregnancy.
Lactation
Advise women
not to breastfeed if they are taking
ADDERALL XR.
MEDICATION GUIDE ADDERALL XR
(Extensive changes; please refer to
labeling)
Approved Drug Label (PDF)
8
Use in Specific Populations
8.1 Pregnancy
(addition
underlined)
Teratogenic Effects
Pregnancy Category C.
Amphetamine, in the enantiomer ratio present in ADDERALL
XR (d- to l- ratio of approximately 3:1), had no apparent effects on
embryofetal morphological development or survival when orally administered to
pregnant rats and rabbits throughout the period of organogenesis at doses of up
to 6 and 16 mg/kg/day, respectively.
…
8.6 Renal Impairment
(new
subsection added)
Due to reduced clearance of amphetamines in patients with
severe renal impairment (GFR 15 to <30 mL/min/1.73m2), the recommended dose
should be reduced. ADDERALL XR is not recommended in patients with ESRD (GFR
< 15 ml/min/1.73m2)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions
underlined)
…
ADDERALL XR may not be right for you or your
child. Before starting ADDERALL XR tell you or your child’s doctor about all
health conditions (or a family history of) including:
…
…
Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
ADDERALL XR administration is
contraindicated in patients with the following conditions:
In
patients known to be hypersensitive to amphetamine, or other components of
ADDERALL XR. Hypersensitivity reactions such as angioedema and anaphylactic
reactions have been reported in patients treated with other amphetamine products.
Patients taking monoamine oxidase inhibitors
(MAOIs), or within 14 days of stopping MAOIs (including MAOIs such as linezolid
or intravenous methylene blue), because of an increased risk of hypertensive
crisis.
5
Warnings and Precautions
5.6 Serotonin Syndrome
Newly
added subsection:
Serotonin syndrome, a potentially
life-threatening reaction, may occur when amphetamines are used in combination
with other drugs that affect the serotonergic neurotransmitter systems such as
MAOIs, selective serotonin reuptake inhibitors (SSRIs), serotonin
norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic
antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St.
John’s Wort. Amphetamines and amphetamine derivatives are known to be
metabolized, to some degree, by cytochrome P450 2D6 (CYP2D6) and display minor
inhibition of CYP2D6 metabolism. The potential for a pharmacokinetic interaction
exists with the co-administration of CYP2D6 inhibitors which may increase the
risk with increased exposure to ADDERALL XR. In these situations, consider an
alternative non-serotonergic drug or an alternative drug that does not inhibit
CYP2D6. Serotonin syndrome symptoms may include mental status changes (e.g.,
agitation, hallucinations, delirium, and coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, dizziness, diaphoresis, flushing,
hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus,
hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea).
Concomitant use of ADDERALL XR with MAOI
drugs is contraindicated.
Discontinue treatment with ADDERALL XR
and any concomitant serotonergic agents immediately if symptoms of serotonin
syndrome occur, and initiate supportive symptomatic treatment. Concomitant use
of ADDERALL XR with other serotonergic drugs or CYP2D6 inhibitors should be
used only if the potential benefit justifies the potential risk. If clinically
warranted, consider initiating ADDERALL XR with lower doses, monitoring
patients for the emergence of serotonin syndrome during drug initiation or
titration, and informing patients of the increased risk for serotonin syndrome.
7
Drug Interactions
Information
has been converted to a table format; please refer to label.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additional
subsections added:
17.6
Serotonin Syndrome
Caution patients about the risk of
serotonin syndrome with concomitant use of ADDERALL XR and other serotonergic
drugs including SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, St. John’s Wort, and with drugs that
impair metabolism of serotonin (in particular MAOIs, both those intended to
treat psychiatric disorders and also others such as linezolid. Advise patients
to contact their
healthcare provider or report to the
emergency room if they experience signs or symptoms of serotonin syndrome.
17.7
Concomitant Medications
Advise patients to notify their
physicians if they are taking, or plan to take, any prescription or
over-the-counter drugs because there is a potential for interactions.
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