Included as part of the PRECAUTIONS section.
Potential For Abuse And Dependence
CNS stimulants, including ADHANSIA XR, other
methylphenidate-containing products, and amphetamines, 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 [see Drug Abuse And
Serious Cardiovascular Events
Sudden death, stroke and myocardial infarction have
occurred in adults treated with CNS stimulant treatment at recommended doses.
Sudden death has occurred in pediatric patients with structural cardiac
abnormalities and other serious cardiac problems taking CNS stimulants at recommended
doses for ADHD. Avoid use in patients with known structural cardiac
abnormalities, cardiomyopathy, serious heart arrhythmia, coronary artery
disease, and other serious heart problems. Further evaluate patients who
develop exertional chest pain, unexplained syncope, or arrhythmias during
treatment during ADHANSIA XR treatment.
Blood Pressure And Heart Rate Increases
CNS stimulants cause an increase in blood pressure (mean
increase approximately 2 to 4 mmHg) and heart rate (mean increase approximately
3 to 6 bpm). Individuals may have larger increases. Monitor all patients for
hypertension and tachycardia.
Psychiatric Adverse Reactions
Exacerbation Of Pre-Existing Psychosis
CNS stimulants may exacerbate symptoms of behavior
disturbance and thought disorder in patients with a pre-existing psychotic
Induction Of A Manic Episode In Patients With Bipolar
CNS stimulants may induce a manic or mixed episode in
patients. Prior to initiating treatment, screen patients for risk factors for
developing a manic episode (e.g., comorbid or history of depressive symptoms or
a family history of suicide, bipolar disorder, or depression).
New Psychotic Or Manic Symptoms
CNS stimulants, at recommended doses, may cause psychotic
or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in
patients without a prior history of psychotic illness or mania. If such
symptoms occur, consider discontinuing ADHANSIA XR. In a pooled analysis of
multiple short-term, placebo-controlled studies of CNS stimulants, psychotic or
manic symptoms occurred in approximately 0.1% of CNS stimulant-treated
patients, compared to 0% in placebo-treated patients.
Prolonged and painful erections, sometimes requiring
surgical intervention, have been reported with methylphenidate products, in
both pediatric and adult patients. Priapism was not reported with drug
initiation but developed after some time on the drug, often subsequent to an
increase in dose. Priapism has also appeared during a period of drug withdrawal
(drug holidays or during discontinuation). Patients who develop abnormally
sustained or frequent and painful erections should seek immediate medical attention.
Peripheral Vasculopathy, Including Raynaud’s Phenomenon
CNS stimulants, including ADHANSIA XR, used to treat ADHD
are associated with peripheral vasculopathy, including Raynaud's phenomenon.
Signs and symptoms are usually intermittent and mild; however, very rare
sequelae include digital ulceration and/or soft tissue breakdown. Effects of
peripheral vasculopathy, including Raynaud's phenomenon, were observed in
post-marketing reports at different times and at therapeutic doses in all age
groups throughout the course of treatment. Signs and symptoms generally improve
after reduction in dose or discontinuation of drug. Careful observation for
digital changes is necessary during treatment with ADHD stimulants. Further
clinical evaluation (e.g., rheumatology referral) may be appropriate for
Long-Term Suppression Of Growth
CNS stimulants have been associated with weight loss and
slowing of growth rate in pediatric patients.
Careful follow-up of weight and height in pediatric patients
ages 7 to 10 years who were randomized to either methylphenidate or
non-medication treatment groups over 14 months, as well as in naturalistic
subgroups of newly methylphenidate-treated and non-medication treated pediatric
patients over 36 months (to the ages of 10 to 13 years), suggests that
consistently medicated pediatric patients (i.e., treatment for 7 days per week
throughout the year) have a temporary slowing in growth rate (on average, a
total of about 2 cm less growth in height and 2.7 kg less growth in weight over
3 years), without evidence of growth rebound during this period of development.
Closely monitor growth (weight and height) in pediatric
patients treated with CNS stimulants, including ADHANSIA XR. Patients who are
not growing or gaining height or weight as expected may need to have their
Allergic-Type Reactions FD&C Yellow No. 5
ADHANSIA XR 45 mg capsules contain FD&C Yellow No. 5
(tartrazine) which may cause allergic-type reactions (including bronchial
asthma) in certain susceptible persons. Although the overall incidence of
FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is
low, it is frequently seen in patients who also have aspirin hypersensitivity [see
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Controlled Substance Status/High Potential For Abuse And Dependence
Advise patients and their caregivers that ADHANSIA XR is
a federally controlled substance, and it can be abused and lead to dependence [see
Drug Abuse And Dependence]. Instruct patients that they should not give
ADHANSIA XR to anyone else. Advise patients to store ADHANSIA XR in a safe
place, preferably locked, to prevent abuse. Advise patients and their
caregivers to comply with laws and regulations on drug disposal. Advise
patients and their caregivers to dispose of remaining, unused, or expired
ADHANSIA XR by a medicine take-back program if available [Warnings and
Precautions (5.1), Abuse and Dependence (9.2, 9.3), How Supplied/Storage and
Instructions For Taking ADHANSIA XR
Advise patients and their caregivers that ADHANSIA XR can
be taken with or without food. For patients who take ADHANSIA XR sprinkled over
a tablespoon of applesauce or yogurt, the contents of the entire capsule should
be consumed immediately or within 10 minutes of mixing; it should not be
stored. Patients should take the applesauce or yogurt with sprinkled beads in
its entirety without chewing. When initiating treatment with ADHANSIA XR,
provide dosage escalation and administration instructions [see DOSAGE AND
Serious Cardiovascular Risks
Advise patients, caregivers, and their family members
that there is a potential serious cardiovascular risk including sudden death,
myocardial infarction, and stroke with ADHANSIA XR use. Instruct patients to
contact a healthcare provider immediately if they develop symptoms such as
exertional chest pain, unexplained syncope, or other symptoms suggestive of
cardiac disease [see WARNINGS AND PRECAUTIONS].
Blood Pressure And Heart Rate Increases
Advise patients and their caregivers that ADHANSIA XR can
cause elevations of their blood pressure and pulse rate [see WARNINGS AND
Advise patients and their caregivers that ADHANSIA XR, at
recommended doses, can cause psychotic or manic symptoms, even in patients
without prior history of psychotic symptoms or mania [see WARNINGS AND
Advise patients, caregivers, and family members of the
possibility of painful or prolonged penile erections (priapism). Instruct them
to seek immediate medical attention in the event of priapism [see WARNINGS
Circulation Problems In Fingers And Toes [Peripheral
Vasculopathy, including Raynaud’s Phenomenon]
- Instruct patients about the risk of peripheral
vasculopathy, including Raynaud's phenomenon, and associated signs and
symptoms: fingers or toes may feel numb, cool, painful, and/or may change color
from pale, to blue, to red.
- Instruct patients to report to their physician any new
numbness, pain, skin color change, or sensitivity to temperature in fingers or
- Instruct patients to call their physician immediately
with any signs of unexplained wounds appearing on fingers or toes while taking
- Further clinical evaluation (e.g., rheumatology referral)
may be appropriate for certain patients [see WARNINGS AND PRECAUTIONS].
Suppression Of Growth
Advise patients, families and caregivers that ADHANSIA XR
may cause slowing of growth and weight loss [see WARNINGS AND PRECAUTIONS].
Advise patients to avoid alcohol while taking ADHANSIA
XR. Consumption of alcohol while taking ADHANSIA XR may result in a more rapid
release of the dose of methylphenidate [see CLINICAL PHARMACOLOGY].
Advise patients that there is a pregnancy exposure
registry that monitors pregnancy outcomes in women exposed to ADHANSIA XR
during pregnancy [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a lifetime carcinogenicity study
carried out in B6C3F1 mice, methylphenidate caused an increase in
hepatocellular adenomas and, in males only, an increase in hepatoblastomas, at
a daily dose of approximately 60 mg/kg/day. This dose is approximately 2 times
the maximum recommended human dose (MRHD) of 85 mg/day given to children on a
mg/m² basis. Hepatoblastoma is a relatively rare rodent malignant tumor type.
There was no increase in total malignant hepatic tumors. The mouse strain used
is sensitive to the development of hepatic tumors, and the significance of
these results to humans is unknown.
Methylphenidate did not cause any increase in tumors in a
lifetime carcinogenicity study carried out in F344 rats; the highest dose used
was approximately 45 mg/kg/day, which is approximately 3 times the MRHD given
to children on a mg/m² basis.
In a 24-week carcinogenicity study in the transgenic
mouse strain p53+/-, which is sensitive to genotoxic carcinogens, there was no
evidence of carcinogenicity. Male and female mice were fed diets containing the
same concentration of methylphenidate as in the lifetime carcinogenicity study;
the high-dose groups were exposed to 60 to 74 mg/kg/day of methylphenidate.
Methylphenidate was not mutagenic in the in vitro Ames
reverse mutation assay or the in vitro mouse lymphoma cell forward mutation
assay. Sister chromatid exchanges and chromosome aberrations were increased,
indicative of a weak clastogenic response, in an in vitro assay in cultured
Chinese Hamster Ovary (CHO) cells. Methylphenidate was negative in an in vivo mouse
bone marrow micronucleus assay.
Impairment Of Fertility
Methylphenidate did not impair fertility in male or
female mice that were fed diets containing the drug in an 18-week Continuous
Breeding study. The study was conducted at doses of up to 160 mg/kg/day,
approximately 5 times the maximum recommended human dose of 85 mg/day given to
adolescents on a mg/m² basis.
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to ADHANSIA XR during pregnancy. Healthcare
providers are encouraged to register patients by calling the National Pregnancy
Registry for Psychostimulants at 1-866-961-2388.
Published studies and post-marketing reports on
methylphenidate use during pregnancy are insufficient to identify a
drug-associated risk of major birth defects, miscarriage or adverse maternal of
fetal outcomes. There are risks to the fetus associated with the use of central
nervous system (CNS) stimulants during pregnancy (see Clinical
Considerations). No effects on morphological development were observed in
embryo-fetal studies with oral administration of methylphenidate to pregnant
rats and rabbits during organogenesis at doses up to 7 and 11 times,
respectively, the maximum recommended human dose (MRHD) of 85 mg/day given to
adolescents on a mg/m² basis. However, fetal spina bifida was observed in
rabbits at a dose 36 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
doses 4 times the MRHD given to adolescents [see Data].
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
Fetal/Neonatal Adverse Reactions
CNS stimulants, such as ADHANSIA XR, can cause vasoconstriction
and thereby decrease placental perfusion. No fetal and/or neonatal adverse
reactions have been reported with the use of therapeutic doses of
methylphenidate during pregnancy; however, premature delivery and low birth
weight infants have been reported in amphetamine-dependent mothers.
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 36 times the maximum recommended human
dose (MRHD) of 85 mg/day given to adolescents on a mg/m² basis. The no effect
level for embryo-fetal development in rabbits was 60 mg/kg/day (11 times the
MRHD given to adolescents on a mg/m² 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 (7 times the MRHD
given to adolescents on a mg/m² 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 given to adolescents on a mg/m² 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 (4
times the MRHD on a mg/m² 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 (equivalent to the MRHD given to adolescents on a mg/m² basis).
Limited published literature, based on breast milk
sampling from five mothers, reports that methylphenidate is present in human
milk, which resulted in infant doses of 0.16% to 0.7% of the maternal
weight-adjusted dosage and a milk/plasma ratio ranging between 1.1 and 2.7.
There are no reports of adverse effects on the breastfed infant and no effects
on milk production. Long-term neurodevelopmental effects on infants from stimulant
exposure are unknown. The developmental and health benefits of breastfeeding
should be considered along with the mother's clinical need for ADHANSIA XR and
any potential adverse effects on the breastfed infant from ADHANSIA XR or from
the underlying maternal condition.
Monitor breastfeeding infants for adverse reactions, such
as agitation, anorexia, and reduced weight gain.
Safety and effectiveness of ADHANSIA XR in pediatric
patients under the age of 6 years have not been established.
The safety and effectiveness of ADHANSIA XR have been
established in one adequate and well-controlled 6-week study in pediatric
patients ages 6 to 12 years, and in one adequate and well-controlled 4-week
study in pediatric patients ages 12 to 17 years [see Clinical Studies].
The long-term efficacy of methylphenidate in pediatric patients has not been
Long Term Suppression Of Growth
Growth should be monitored during treatment with
stimulants, including ADHANSIA XR. Pediatric patients who are not growing or
gaining weight as expected may need to have their treatment interrupted [see WARNINGS
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 3 times the maximum recommended human dose (MRHD) of
85 mg/day given to children on a mg/m² 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 3 times
the MRHD of 85 mg/day given to children on a mg/m² basis) or greater, and a
deficit in the acquisition of a specific learning task was observed in females
exposed to the highest dose (6 times the MRHD given to children on a mg/m² basis).
The no effect level for juvenile neurobehavioral development in rats was 5
mg/kg/day (approximately 0.25 times the MRHD given to children on a mg/m² basis).
The clinical significance of the long-term behavioral effects observed in rats
ADHANSIA XR has not been studied in the patients over the
age of 72 years.