Included as part of the PRECAUTIONS section.
Sudden Death And Preexisting Structural Cardiac
Abnormalities Or Other Serious Heart Problems
Children and Adolescents
Sudden death has been reported in association with CNS
stimulant treatment at usual doses in children and adolescents with structural
cardiac abnormalities or other serious heart problems. Although some serious
heart problems alone carry an increased risk of sudden death, stimulant
products generally should not be used in children or adolescents with known
serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm
abnormalities, or other serious cardiac problems that may place them at
increased vulnerability to the sympathomimetic effects of a stimulant drug.
Sudden death, stroke, and myocardial infarction have been
reported in adults taking stimulant drugs at usual doses for ADHD. Although the
role of stimulants in these adult cases is also unknown, adults have a greater
likelihood than children of having serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or
other serious cardiac problems. Adults with such abnormalities should also
generally not be treated with stimulant drugs.
Hypertension And Other Cardiovascular Conditions
Stimulant medications cause a modest increase in average
blood pressure (about 2–4 mmHg) and average heart rate (about 3–6 bpm), and
individuals may have larger increases. While the mean changes alone would not
be expected to have short-term consequences, all patients should be monitored
for larger changes in heart rate and blood pressure. Caution is indicated in
treating patients whose underlying medical conditions might be compromised by
increases in blood pressure or heart rate, e.g., those with preexisting hypertension,
heart failure, recent myocardial infarction, or ventricular arrhythmia.
Assessing Cardiovascular Status In Patients Being Treated
With Stimulant Medications
Children, adolescents, or adults who are being considered
for treatment with stimulant medications should have a careful history
(including assessment for a family history of sudden death or ventricular
arrhythmia) and physical exam to assess for the presence of cardiac disease,
and should receive further cardiac evaluation if findings suggest such disease
(e.g., electrocardiogram and echocardiogram). Patients who develop symptoms
such as exertional chest pain, unexplained syncope, or other symptoms
suggestive of cardiac disease during stimulant treatment should undergo a
prompt cardiac evaluation.
Administration of stimulants may exacerbate symptoms of
behavior disturbance and thought disorder in patients with a preexisting
Particular care should be taken in using stimulants to
treat ADHD in patients with comorbid bipolar disorder because of concern for
possible induction of a mixed/manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid depressive
symptoms should be adequately screened to determine if they are at risk for
bipolar disorder; such screening should include a detailed psychiatric history,
including a family history of suicide, bipolar disorder, and depression.
Emergence Of New Psychotic Or Manic Symptoms
Treatment emergent psychotic or manic symptoms, e.g.,
hallucinations, delusional thinking, or mania in children and adolescents
without a prior history of psychotic illness or mania can be caused by
stimulants at usual doses. If such symptoms occur, consideration should be
given to a possible causal role of the stimulant, and discontinuation of
treatment may be appropriate. In a pooled analysis of multiple short-term,
placebo-controlled studies, such symptoms occurred in about 0.1% (4 patients
with events out of 3,482 exposed to methylphenidate or amphetamine for several
weeks at usual doses) of stimulant-treated patients compared to 0 in
Aggressive behavior or hostility is often observed in
children and adolescents with ADHD, and has been reported in clinical trials
and the post marketing experience of some medications indicated for the
treatment of ADHD. Although there is no systematic evidence that stimulants
cause aggressive behavior or hostility, patients beginning treatment for ADHD
should be monitored for the appearance of or worsening of aggressive behavior
Long-Term Suppression Of Growth
Careful follow-up of weight and height in children ages 7
to 10 years who were randomized to either methylphenidate or nonmedication
treatment groups over 14 months, as well as in naturalistic subgroups of newly
methylphenidate-treated and nonmedication treated children over 36 months (to
the ages of 10 to 13 years), suggests that consistently medicated children
(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. In the 7-week, double-blind,
placebo-controlled study of Focalin XR, the mean weight gain was greater for
patients receiving placebo (+0.4 kg) than for patients receiving Focalin XR
(-0.5 kg). Published data are inadequate to determine whether chronic use of
amphetamines may cause a similar suppression of growth, however, it is
anticipated that they likely have this effect as well. Therefore, growth should
be monitored during treatment with stimulants, and patients who are not growing
or gaining height or weight as expected may need to have their treatment
There is some clinical evidence that stimulants may lower
the convulsive threshold in patients with prior history of seizures, in
patients with prior EEG abnormalities in absence of seizures, and, very rarely,
in patients without a history of seizures and no prior EEG evidence of
seizures. In the presence of seizures, the drug should be discontinued.
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
Stimulants, including Focalin 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 postmarketing
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 certain
Difficulties with accommodation and blurring of vision
have been reported with stimulant treatment.
Use In Children Under Six Years Of Age
Focalin XR should not be used in children under 6 years
of age, since safety and efficacy in this age group have not been established.
Periodic CBC, differential, and platelet counts are
advised during prolonged therapy.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Information For Patients
Prescribers or other health professionals should inform
patients, their families, and their caregivers about the benefits and risks
associated with treatment with dexmethylphenidate and should counsel them in
its appropriate use. A patient Medication Guide is available for Focalin XR.
The prescriber or health professional should instruct patients, their families,
and their caregivers to read the Medication Guide and should assist them in
understanding its contents. Patients should be given the opportunity to discuss
the contents of the Medication Guide and to obtain answers to any questions
they may have. The complete text of the Medication Guide is reprinted at the
end of this document.
Advise patients, caregivers, and family members of the
possibility of painful or prolonged penile erections (priapism). Instruct the
patient 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 beginning treatment with Focalin XR
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.
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
Lifetime carcinogenicity studies have not been carried
out with dexmethylphenidate. In a lifetime carcinogenicity study carried out in
B6C3F1 mice, racemic 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. 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.
Racemic 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.
In a 24-week study of racemic methylphenidate in the
transgenic mouse strain p53+/-, which is sensitive to genotoxic carcinogens,
there was no evidence of carcinogenicity. Mice were fed diets containing the
same concentrations as in the lifetime carcinogenicity study; the high-dose
group was exposed to 60–74 mg/kg/day of racemic methylphenidate.
Dexmethylphenidate was not mutagenic in the in vitro Ames
reverse mutation assay, the in vitro mouse lymphoma cell forward mutation
assay, or the in vivo mouse bone marrow micronucleus test.
Racemic methylphenidate was not mutagenic in the in vitro
Ames reverse mutation assay or the in vitro mouse lymphoma cell forward
mutation assay, and was negative in vivo in the mouse bone marrow micronucleus
assay. However, sister chromatid exchanges and chromosome aberrations were
increased, indicative of a weak clastogenic response, in an in vitro assay of
racemic methylphenidate in cultured Chinese Hamster Ovary (CHO) cells.
Impairment of Fertility
Racemic 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.
Use In Specific Populations
Pregnancy Category C
There are no adequate and well controlled studies of
Focalin in pregnant women. Dexmethylphenidate did not cause major malformations
in rats or rabbits; however, it did cause delayed skeletal ossification and
decreased postweaning weight gain in rats. Focalin XR should be used during
pregnancy only if the potential benefit justifies the potential risk to the
In studies conducted in rats and rabbits,
dexmethylphenidate was administered orally at doses of up to 20 and 100 mg/kg/day,
respectively, during the period of organogenesis. No evidence of teratogenic
activity was found in either the rat or rabbit study; however, delayed fetal
skeletal ossification was observed at the highest dose level in rats. When
dexmethylphenidate was administered to rats throughout pregnancy and lactation
at doses of up to 20 mg/kg/day, postweaning body weight gain was decreased in
male offspring at the highest dose, but no other effects on postnatal
development were observed. At the highest doses tested, plasma levels (AUCs) of
dexmethylphenidate in pregnant rats and rabbits were approximately 5 and 1
times, respectively, those in adults dosed with 20 mg/day.
Racemic methylphenidate has been shown to have
teratogenic effects in rabbits when given in doses of 200 mg/kg/day throughout
Labor And Delivery
Focalin XR has not been studied in labor and delivery.
It is not known whether dexmethylphenidate is excreted in
human milk. Because many drugs are excreted in human milk, caution should be
exercised if Focalin XR is administered to a nursing woman. Information from 4
published case reports on the use of racemic methylphenidate during
breastfeeding suggest that at maternal doses of 35–80 mg/day, milk
concentrations of methylphenidate range from undetectable to 15.4 ng/mL. Based
on these limited data, the calculated infant daily dose for an exclusively
breastfed infant would be about 0.4–2.9 μg/kg/day or about 0.2–0.7% of the
maternal weight adjusted dose.
The safety and efficacy of Focalin XR in children under 6
years old have not been established. Long-term effects of Focalin in children
have not been well established [see WARNINGS AND PRECAUTIONS].
In a study conducted in young rats, racemic
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 maximum recommended human dose [MRHD] of racemic
methylphenidate on a mg/m² basis) or greater, and a deficit in the acquisition
of a specific learning task was seen in females exposed to the highest dose (12
times the racemic MRHD on a mg/m² basis). The no effect level for juvenile
neurobehavioral development in rats was 5 mg/kg/day (half the racemic MRHD on a
mg/m² basis). The clinical significance of the long-term behavioral effects
observed in rats is unknown.
Focalin XR has not been studied in the geriatric