Approved Drug Label (PDF)
Boxed Warning
Additions and/or
revisions underlined:
WARNING: ABUSE,
MISUSE, AND ADDICTION
APTENSIO 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 APTENSIO 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
APTENSIO 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
APTENSIO 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) and Drug Abuse and Dependence
(9.2)].
5
Warnings and Precautions
5.1 Abuse, Misuse, and Addiction
Additions and/or
revisions underlined:
APTENSIO XR has a high
potential for abuse and misuse. The use of APTENSIO XR exposes
individuals to the risks of abuse and misuse, which can lead to
the development of a substance use disorder, including addiction.
APTENSIO
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 APTENSIO 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 APTENSIO 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 APTENSIO XR in a safe place, preferably locked,
and instruct patients to not give APTENSIO XR to anyone else. Throughout
APTENSIO XR treatment, reassess each patient’s risk of abuse, misuse,
and addiction and frequently monitor for signs and symptoms of abuse, misuse,
and addiction.
5.10Motor and Verbal Tics, and Worsening of Tourette’s Syndrome
New subsection
added:
CNS stimulants, including methylphenidate, 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 APTENSIO XR, assess the family
history and clinically evaluate patients for tics or Tourette’s syndrome.
Regularly monitor APTENSIO XR-treated patients for the emergence or worsening
of tics or Tourette’s syndrome, and discontinue treatment if clinically
appropriate.
5.7 Long-Term Suppression of Growth in Pediatric Patients
Additions and/or
revisions underlined:
…
APTENSIO XR is not approved for use in pediatric
patients below 6 years of age [see Use in Specific Popultations (8.4)].
5.8 Acute Angle Closure Glaucoma
New subsection
added:
There have been reports of angle closure glaucoma
associated with methylphenidate treatment.
A though the
mechanism is not clear, APTENSIO XR-treated patients considered at risk for
acute angle closure glaucoma (e.g., patients with significant hyperopia) should
be evaluated by an ophthalmologist.
5.9 Increased Intraocular Pressure and Glaucoma
New subsection
added:
There have been reports of an elevation of
intraocular pressure (IOP) associated with methylphenidate treatment [see
Adverse Reactions (6.2)].
Prescribe APTENSIO XR to patients with open-angle
glaucoma or abnormally increased IOP only if the benefit of treatment is
considered to outweigh the risk. Closely monitor APTENSIO XR-treated patients
with a history of abnormally increased IOP or open angle glaucoma.
6
Adverse Reactions
Additions and/or
revisions underlined:
The following are discussed in more detail in other
sections of the labeling:
Abuse, Misuse, and Addiction [see
Boxed Warning, Warnings and Precautions (5.1), and Drug Abuse and Dependence
(9.2, 9.3)]
…
Acute Angle Closure
Glaucoma [see Warnings and Precautions (5.8)]
Increased Intraocular
Pressure and Glaucoma [see Warnings and Precautions (5.9)]
Motor and Verbal Tics, and
Worsening of Tourette’s Syndrome [see Warnings and Precautions (5.10)]
6.2 Postmarketing
Experience
Additions
and/or revisions underlined:
…
Eye Disorders: Diplopia, Increased
intraocular pressure, Mydriasis, Visual impairment
…
Nervous System: Convulsion,
Grand mal convulsion, Dyskinesia, serotonin syndrome in combination with
serotonergic drugs, Motor and Verbal Tics
…
7
Drug Interactions
Additions
and/or revisions underlined:
Halogenated
Anesthetics
Concomitant
use of halogenated anesthetics and APTENSIO XR may increase the risk of sudden
blood pressure and heart rate increase during surgery. Avoid use of APTENSIO XR
in patients being treated with anesthetics on the day of surgery.
…
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 APTENSIO 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 APTENSIO XR in a safe place,
preferably locked, and instruct patients to not give APTENSIO XR to anyone
else.
…
Long-Term Suppression of Growth in Pediatric
Patients
Advise patients that APTENSIO XR may cause slowing
of growth and weight loss [see Warnings
and Precautions (5.7)].
Increased Intraocular Pressure (IOP) and Glaucoma
Advise patients that IOP and glaucoma may occur
during treatment with APTENSIO XR [see
Warnings and Precautions (5.9)].
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 APTENSIO 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 (5.10)].
…
Pregnancy Registry
Advise patients that there is a pregnancy exposure
registry that monitors pregnancy outcomes in women exposed to APTENSIO XR
during pregnancy [see Use in Specific
Populations (8.1)].
MEDICATION GUIDE
Medication
Guide has undergone extensive changes; please refer to label.
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Serious Cardiovascular Reactions
(Revision of
subsection title)
5.6 Peripheral Vasculopathy, including Raynaud’s Phenomenon
(Additions and/or
revisions are underlined)
CNS stimulants, including APTENSIO
XR, used to treat ADHD are associated with peripheral vasculopathy, including Raynaud’s
phenomenon...
6
Adverse Reactions
(Additions and/or
revisions are underlined)
The following are discussed
in more detail in other sections
of the labeling:
Abuse and Dependence
Hypertensive Crisis with Concomintant Use of Monoamine Oxidase Inhibitors
Serious Cardiovascular Reactions
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or
revisions are underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to APTENSIO XR during
pregnancy. Healthcare providers are encouraged to register
patients by calling
the National Pregnancy
Registry for Psychostimulants at 1-866-961-2388.
Risk Summary
Limited published studies
report on the use of
methylphenidate in pregnant
women; however, the data are insufficient to inform any drug-associated risks. No
effects on morphological development were observed in embryo-fetal development studies with oral administration of methylphenidate to pregnant rats and
rabbits during organogenesis
at
doses up to 10 and 15 times, respectively, the maximum recommended human dose (MRHD) of 60
mg/day given to adolescents on a mg/m^2 basis. However,
spina bifida was observed
in rabbits
at
a dose 52 times the MRHD
given to adolescents. A decrease
in pup body weight was
observed in a pre-and post-natal development study with
oral administration of methylphenidate to rats throughout pregnancy and lactation
at
the highest dose of 60 mg/kg/day (6 times the MRHD given to
adolescents).
Data
Animal Data
In embryo-fetal development studies conducted
in rats and rabbits, methylphenidate was
administered orally at doses
of up to 75 and 200 mg/kg/day, respectively, during the period
of organogenesis. Malformations (increased incidence of fetal spina bifida) were observed in rabbits at the highest dose, which is approximately 52
times the maximum recommended human dose (MRHD) of 60 mg/day given
to adolescents on a mg/m^2 basis.
The no effect level for
embryo-fetal development in rabbits was 60 mg/kg/day (15
times the MRHD given to
adolescents on a mg/m^2 basis). There was no evidence of morphological development effects in rats, although increased incidences of fetal skeletal variations were seen at the
highest dose level (10 times the
MRHD of 60 mg/day given to adolescents on a mg/m^2 basis), which was also maternally toxic.
The no effect level for
embryo-fetal development in rats
was 25 mg/kg/day (2 times the MRHD on a mg/m^2 basis). When methylphenidate was administered to rats
throughout pregnancy and lactation at doses of up to 45 mg/kg/day,
offspring body weight
gain was decreased at the highest dose (6
times the MRHD of 60 mg/day given to adolescents on a mg/m^2 basis), but no other effects on postnatal development were observed. The no
effect level for pre- and
postnatal development in rats was 15 mg/kg/day (1.5 times the
MRHD given to adolescents on a
mg/m^2 basis).
8.4 Pediatric Use
(Additions and/or
revisions are underlined)
The safety and effectiveness
of APTENSIO
XR in pediatric patients under 6 years have
not been established.
Safety and efficacy
of APTENSIO XR
were
evaluated in a multicenter,
placebo-controlled, double-blind, parallel group study in 119
children 4 to <6 years of
age with ADHD followed by a 12-month open-label extension in 44 of these children. In these studies,
patients experienced high rates of adverse
reactions, most notably
weight loss. Comparing
weights prior to
initiation of APTENSIO
XR (in the safety and efficacy
study) to weights after 12 months
of treatment (in the open-label extension), 20 of 39
patients with data (50%) had lost enough weight to decrease 10 or more percentiles on a Centers for
Disease Control growth chart for
weight. In addition, systemic
drug exposures in patients 4 to <6 years of
age were higher than
those observed in older
children and adolescents at the same
dose (2 to 3 fold higher Cmax and
AUC). Therefore, the benefits
of APTENSIO XR do not outweigh the risks in pediatric patients
4 to <6 years of age.
Juvenile Animal Toxicity Data
Rats
treated with methylphenidate early in the
postnatal period through sexual maturation demonstrated a decrease in spontaneous locomotor activity in adulthood. A deficit in acquisition of a specific
learning task was observed in females only.
The doses at which these findings were observed are at least 6 times
the maximum recommended human dose (MRHD)
of 60 mg/day given to children on a
mg/m^2 basis.
In
the study conducted in young rats, methylphenidate was administered orally at doses of up to
100 mg/kg/day for 9 weeks, starting early in the postnatal
period (postnatal day 7) and continuing through sexual maturity
(postnatal week 10). When these animals were tested as adults (postnatal weeks
13-14), decreased spontaneous locomotor activity
was observed in males
and females previously treated with 50 mg/kg/day (approximately 6 times the MRHD of 60 mg/day given
to children on a mg/m^2 basis)
or greater, and a deficit in the acquisition of a specific learning task was observed
in females exposed to the highest dose (8 times the MRHD given to
children on a mg/m^2 basis). The no effect level for juvenile neurobehavioral development in rats was 5 mg/kg/day (approximately 0.5 times the MRHD
given to children on a mg/m^2 basis). The clinical significance of the long-term behavioral effects observed in rats is unknown.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
(Newly added information; please refer to label
for complete information)
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