Overdose
Signs and Symptoms
Signs and symptoms of acute overdosage, resulting
principally from overstimulation of the central nervous system and from
excessive sympathomimetic effects, may include the following: vomiting,
agitation, tremors, hyperreflexia, muscle twitching, convulsions (may be
followed by coma), euphoria, confusion, hallucinations, delirium, sweating,
flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac
arrhythmias, hypertension, mydriasis, and dryness of mucous membranes.
Poison Control Center
Consult with a Certified Poison Control Center regarding
treatment for up-to-date guidance and advice.
Recommended Treatment
As with the management of all overdosage, the possibility
of multiple drug ingestion should be considered.
When treating overdose, practitioners should bear in mind
that there is a prolonged release of methylphenidate from Ritalin LA® (methylphenidate
hydrochloride) extended-release capsules.
Treatment consists of appropriate supportive measures.
The patient must be protected against self-injury and against external stimuli
that would aggravate overstimulation already present. Gastric contents may be
evacuated by gastric lavage as indicated. Before performing gastric lavage,
control agitation and seizures if present and protect the airway. Other
measures to detoxify the gut include administration of activated charcoal and a
cathartic. Intensive care must be provided to maintain adequate circulation and
respiratory exchange; external cooling procedures may be required for
hyperpyrexia.
Efficacy of peritoneal dialysis or extracorporeal
hemodialysis for methylphenidate overdosage has not been established; also,
dialysis is considered unlikely to be of benefit due to the large volume of
distribution of methylphenidate.
Undesirable effects
The clinical program for Ritalin LA® (methylphenidate
hydrochloride) extended-release capsules consisted of six studies: two
controlled clinical studies conducted in children with ADHD aged 6-12 years and
four clinical pharmacology studies conducted in healthy adult volunteers. These
studies included a total of 256 subjects; 195 children with ADHD and 61 healthy
adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per
day. Safety of Ritalin LA was assessed by evaluating frequency and nature of
adverse events, routine laboratory tests, vital signs, and body weight.
Adverse events during exposure were obtained primarily by
general inquiry and recorded by clinical investigators using terminology of
their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without
first grouping similar types of events into a smaller number of standardized
event categories. In the tables and listings that follow, MEDRA terminology has
been used to classify reported adverse events. The stated frequencies of
adverse events represent the proportion of individuals who experienced, at
least once, a treatment-emergent adverse event of the type listed. An event was
considered treatment emergent if it occurred for the first time or worsened
while receiving therapy following baseline evaluation.
Adverse Events in a Double-Blind, Placebo-Controlled
Clinical Trial with Ritalin LA
Treatment-Emergent Adverse Events
A placebo-controlled, double-blind, parallel-group study
was conducted to evaluate the efficacy and safety of Ritalin LA in children
with ADHD aged 6-12 years. All subjects received Ritalin LA for up to 4 weeks,
and had their dose optimally adjusted, prior to entering the double-blind phase
of the trial. In the two-week double-blind treatment phase of this study,
patients received either placebo or Ritalin LA at their individually-titrated
dose (range 10 mg-40 mg).
The prescriber should be aware that these figures cannot
be used to predict the incidence of adverse events in the course of usual
medical practice where patient characteristics and other factors differ from
those which prevailed in the clinical trials. Similarly, the cited frequencies
cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures,
however, do provide the prescribing physician with some basis for estimating
the relative contribution of drug and non-drug factors to the adverse event
incidence rate in the population studied.
Adverse events with an incidence > 5% during the
initial four-week single-blind Ritalin LA titration period of this study were
headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.
Treatment-emergent adverse events with an incidence
> 2% among Ritalin LA-treated subjects, during the two-week double-blind
phase of the clinical study, were as follows:
| Preferred term |
Ritalin LA®
N=65
N (%) |
Placebo
N=71
N (%) |
| Anorexia |
2 (3.1) |
0 (0.0) |
| Insomnia |
2 (3.1) |
0 (0.0) |
Adverse Events Associated with
Discontinuation of Treatment
In the two-week double-blind
treatment phase of a placebo-controlled parallel-group study in children with
ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an
adverse event (depression).
In the single-blind titration period of this study,
subjects received Ritalin LA for up to 4 weeks. During this period a total of
six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse
events leading to discontinuation were anger (in 2 patients), hypomania,
anxiety, depressed mood, fatigue, migraine and lethargy.
Adverse Events with Other Methylphenidate HCl Dosage
Forms
Nervousness and insomnia are the most common adverse
reactions reported with other methylphenidate products. In children, loss of
appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and
tachycardia may occur more frequently; however, any of the other adverse
reactions listed below may also occur.
Other reactions include:
Cardiac: angina, arrhythmia, palpitations, pulse
increased or decreased, tachycardia
Gastrointestinal: abdominal pain, nausea
Immune: hypersensitivity reactions including skin
rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme
with histopathological findings of necrotizing vasculitis, and thrombocytopenic
purpura.
Metabolism/Nutrition: anorexia, weight loss during
prolonged therapy
Nervous System: dizziness, drowsiness, dyskinesia,
headache, rare reports of Tourette's syndrome, toxic psychosis
Vascular: blood pressure increased or decreased;
cerebrovascular vasculitis; cerebral occlusions; cerebral hemorrhages and
cerebrovascular accidents
Although a definite causal relationship has not been
established, the following have been reported in patients taking
methylphenidate:
Blood/Lymphatic: leukopenia and/or anemia
Hepatobiliary: abnormal liver function, ranging
from transaminase elevation to hepatic coma
Psychiatric: transient depressed mood, aggressive
behavior
Skin/Subcutaneous: scalp hair loss
Very rare reports of neuroleptic malignant syndrome (NMS)
have been received, and, in most of these, patients were concurrently receiving
therapies associated with NMS. In a single report, a ten-year-old boy who had
been taking methylphenidate for approximately 18 months experienced an NMS-like
event within 45 minutes of ingesting his first dose of venlafaxine. It is
uncertain whether this case represented a drug-drug interaction, a response to
either drug alone, or some other cause.
Drug Abuse And Dependence
Ritalin LA® (methylphenidate hydrochloride)
extended-release capsules, like other products containing methylphenidate, is a
Schedule II controlled substance. (See WARNINGS for boxed warning containing
drug abuse and dependence information.)
Pharmacodynamic properties
Methylphenidate hydrochloride,
the active ingredient in Ritalin LA® (methylphenidate hydrochloride)
extended-release capsules, is a central nervous system (CNS) stimulant. The
mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD)
is not known. Methylphenidate is thought to block the reuptake of
norepinephrine and dopamine into the presynaptic neuron and increase the release
of these monoamines into the extraneuronal space. Methylphenidate is a racemic
mixture comprised of the d-and l-threo enantiomers. The d-threo enantiomer is
more pharmacologically active than the l-threo enantiomer.
Pharmacokinetic properties
Absorption
Ritalin LA produces a bi-modal plasma concentration-time
profile (i.e., two distinct peaks approximately four hours apart) when orally
administered to children diagnosed with ADHD and to healthy adults. The initial
rate of absorption for Ritalin LA is similar to that of Ritalin tablets as
shown by the similar rate parameters between the two formulations, i.e., initial
lag time (Tlag), first peak concentration (Cmax1), and time to the first peak
(Tmax1), which is reached in 1-3 hours. The mean time to the interpeak minimum
(Tminip), and time to the second peak (Tmax2) are also similar for Ritalin LA
given once daily and Ritalin tablets given in two doses 4 hours apart (see
Figure 1 and Table 1), although the ranges observed are greater for Ritalin LA.
Ritalin LA given once daily exhibits a lower second peak
concentration (Cmax2), higher interpeak minimum concentrations (Cminip), and
less peak and trough fluctuations than Ritalin tablets given in two doses given
4 hours apart. This is due to an earlier onset and more prolonged absorption
from the delayed-release beads (see Figure 1 and Table 1).
The relative bioavailability of Ritalin LA given once
daily is comparable to the same total dose of Ritalin tablets given in two
doses 4 hours apart in both children and in adults.
Figure 1: Mean plasma concentration time-profile of
methylphenidate after a single dose of Ritalin LA® 40 mg q.d. and
Ritalin® 20 mg given in two doses four hours apart
Table 1: Mean ± SD and range of pharmacokinetic
parameters of methylphenidate after a single dose of Ritalin LA® and
Ritalin® given in two doses 4 hours apart
| Population |
Children |
AdultMales |
| Formulation Dose |
Ritalin® 10 mg & 10 mg |
Ritalin LA® 20 mg |
Ritalin® 10 mg & 10 mg |
Ritalin LA® 20 mg |
| N |
21 |
18 |
9 |
8 |
| Tlag (h) |
0.24 ± 0.44 |
0.28 ± 0.46 |
1.0 ± 0.5 |
0.7 ± 0.2 |
| 0 - 1 |
0 - 1 |
0.7 - 1.3 |
0.3 - 1.0 |
| Tmax1 (h) |
1.8 ± 0.6 |
2.0 ± 0.8 |
1.9 ± 0.4 |
2.0 ± 0.9 |
| 1 - 3 |
1 - 3 |
1.3 - 2.7 |
1.3 - 4.0 |
| Cmax1 (ng/mL) |
10.2 ± 4.2 |
10.3 ± 5.1 |
4.3 ± 2.3 |
5.3 ± 0.9 |
| 4.2 - 20.2 |
5.5 - 26.6 |
1.8 - 7.5 |
3.8 - 6.9 |
| Tminip (h) |
4.0 ± 0.2 |
4.5 ± 1.2 |
3.8 ± 0.4 |
3.6 ± 0.6 |
| 4 - 5 |
2 - 6 |
3.3 - 4.3 |
2.7 - 4.3 |
| Cminip (ng/mL) |
5.8 ± 2.7 |
6.1 ± 4.1 |
1.2 ± 1.4 |
3.0 ± 0.8 |
| 3.1 - 14.4 |
2.9 - 21.0 |
0.0 - 3.7 |
1.7 - 4.0 |
| Tmax2 (h) |
5.6 ± 0.7 |
6.6 ± 1.5 |
5.9 ± 0.5 |
5.5 ± 0.8 |
| 5 - 8 |
5 - 11 |
5.0 - 6.5 |
4.3 - 6.5 |
| Cmax2 (ng/mL) |
15.3 ± 7.0 |
10.2 ± 5.9 |
5.3 ± 1.4 |
6.2 ± 1.6 |
| 6.2 - 32.8 |
4.5 - 31.1 |
3.6 - 7.2 |
3.9 - 8.3 |
| AUC(0-∞) (ng/mL x h-1) |
102.4 ± 54.6 |
86.6 ± 64.0a |
37.8 ± 21.9 |
45.8 ± 10.0 |
| 40.5 - 261.6 |
43.3 - 301.44 |
14.3 - 85.3 |
34.0 - 61.6 |
| t½ (h) |
2.5 ± 0.8 |
2.4 ± 0.7a |
3.5 ± 1.9 |
3.3 ± 0.4 |
| 1.8 - 5.3 |
1.5 - 4.0 |
1.3 - 7.7 |
3.0 - 4.2 |
| aN = 15 |
Dose Proportionality
After oral administration of
Ritalin LA 20 mg and 40 mg capsules to adults there is a slight upward trend in
the methylphenidate area under the curve (AUC) and peak plasma concentrations
(Cmax1 and Cmax2).
Distribution
Binding to plasma proteins is
low (10%-33%). The volume of distribution was 2.65±1.11 L/kg for
dmethylphenidate and 1.80±0.91 L/kg for l-methylphenidate.
Metabolism
The absolute oral
bioavailability of methylphenidate in children was 22±8% for d-methylphenidate
and 5±3% for l-methylphenidate, suggesting pronounced presystemic metabolism.
Biotransformation of methylphenidate by the carboxylesterase CES1A1 is rapid
and extensive leading to the main, deesterified metabolite
α-phenyl-2-piperidine acetic acid (ritalinic acid). Only small amounts of
hydroxylated metabolites (e.g., hydroxymethylphenidate and hydroxyritalinic
acid) are detectable in plasma. Therapeutic activity is principally due to the
parent compound.
Elimination
In studies with Ritalin LA and
Ritalin tablets in adults, methylphenidate from Ritalin tablets is eliminated
from plasma with an average half-life of about 3.5 hours, (range 1.3 - 7.7 hours).
In children the average half-life is about 2.5 hours, with a range of about 1.5
- 5.0 hours. The rapid half-life in both children and adults may result in
unmeasurable concentrations between the morning and mid-day doses with
Ritalin tablets. No accumulation of methylphenidate is expected following
multiple once a day oral dosing with Ritalin LA. The half-life of ritalinic
acid is about 3-4 hours.
The systemic clearance is 0.40±0.12 L/h/kg for
d-methylphenidate and 0.73±0.28 L/h/kg for lmethylphenidate. After oral
administration of an immediate release formulation of methylphenidate, 78%-97%
of the dose is excreted in the urine and 1%-3% in the feces in the form of
metabolites within 48-96 hours. Only small quantities ( < 1%) of unchanged
methylphenidate appear in the urine. Most of the dose is excreted in the urine
as ritalinic acid (60%-86%), the remainder being accounted for by minor
metabolites.
Food Effects
Administration times relative to meals and meal
composition may need to be individually titrated.
When Ritalin LA was administered with a high fat
breakfast to adults, Ritalin LA had a longer lag time until absorption began
and variable delays in the time until the first peak concentration, the time
until the interpeak minimum, and the time until the second peak. The first peak
concentration and the extent of absorption were unchanged after food relative
to the fasting state, although the second peak was approximately 25% lower. The
effect of a high fat lunch was not examined.
There were no differences in the pharmacokinetics of
Ritalin LA when administered with applesauce, compared to administration in the
fasting condition. There is no evidence of dose dumping in the presence or
absence of food.
For patients unable to swallow the capsule, the contents
may be sprinkled on applesauce and administered (see DOSAGE AND
ADMINISTRATION).
Alcohol Effect
Alcohol may exacerbate the adverse CNS effects of
psychoactive drugs, including Ritalin. It is therefore advisable for patients
to abstain from alcohol during treatment. An in vitro study was conducted to
explore the effect of alcohol on the release characteristics of methylphenidate
from the Ritalin LA® 40 mg capsule dosage form. At an alcohol concentration of
40% there was a 98% release of methylphenidate in the first hour. The results
with the 40 mg capsule are considered to be representative of the other
available capsule strengths.
Fertility, pregnancy and lactation
Pregnancy Category C
In 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. Teratogenic effects (increased incidence of
fetal spina bifida) were observed in rabbits at the highest dose, which is
approximately 40 times the maximum recommended human dose (MRHD) on a mg/m² basis. The no effect level for embryo-fetal development in rabbits was 60
mg/kg/day (11 times the MRHD on a mg/m² basis). There was no
evidence of specific teratogenic activity in rats, although increased
incidences of fetal skeletal variations were seen at the highest dose level (7
times the MRHD 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 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 (equal to the MRHD on a mg/m² basis).
Adequate and well-controlled studies in pregnant women
have not been conducted. Ritalin LA should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
The clinical program for Ritalin LA® (methylphenidate
hydrochloride) extended-release capsules consisted of six studies: two
controlled clinical studies conducted in children with ADHD aged 6-12 years and
four clinical pharmacology studies conducted in healthy adult volunteers. These
studies included a total of 256 subjects; 195 children with ADHD and 61 healthy
adult volunteers. The subjects received Ritalin LA in doses of 10-40 mg per
day. Safety of Ritalin LA was assessed by evaluating frequency and nature of
adverse events, routine laboratory tests, vital signs, and body weight.
Adverse events during exposure were obtained primarily by
general inquiry and recorded by clinical investigators using terminology of
their own choosing. Consequently, it is not possible to provide a meaningful
estimate of the proportion of individuals experiencing adverse events without
first grouping similar types of events into a smaller number of standardized
event categories. In the tables and listings that follow, MEDRA terminology has
been used to classify reported adverse events. The stated frequencies of
adverse events represent the proportion of individuals who experienced, at
least once, a treatment-emergent adverse event of the type listed. An event was
considered treatment emergent if it occurred for the first time or worsened
while receiving therapy following baseline evaluation.
Adverse Events in a Double-Blind, Placebo-Controlled
Clinical Trial with Ritalin LA
Treatment-Emergent Adverse Events
A placebo-controlled, double-blind, parallel-group study
was conducted to evaluate the efficacy and safety of Ritalin LA in children
with ADHD aged 6-12 years. All subjects received Ritalin LA for up to 4 weeks,
and had their dose optimally adjusted, prior to entering the double-blind phase
of the trial. In the two-week double-blind treatment phase of this study,
patients received either placebo or Ritalin LA at their individually-titrated
dose (range 10 mg-40 mg).
The prescriber should be aware that these figures cannot
be used to predict the incidence of adverse events in the course of usual
medical practice where patient characteristics and other factors differ from
those which prevailed in the clinical trials. Similarly, the cited frequencies
cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures,
however, do provide the prescribing physician with some basis for estimating
the relative contribution of drug and non-drug factors to the adverse event
incidence rate in the population studied.
Adverse events with an incidence > 5% during the
initial four-week single-blind Ritalin LA titration period of this study were
headache, insomnia, upper abdominal pain, appetite decreased, and anorexia.
Treatment-emergent adverse events with an incidence
> 2% among Ritalin LA-treated subjects, during the two-week double-blind
phase of the clinical study, were as follows:
| Preferred term |
Ritalin LA®
N=65
N (%) |
Placebo
N=71
N (%) |
| Anorexia |
2 (3.1) |
0 (0.0) |
| Insomnia |
2 (3.1) |
0 (0.0) |
Adverse Events Associated with
Discontinuation of Treatment
In the two-week double-blind
treatment phase of a placebo-controlled parallel-group study in children with
ADHD, only one Ritalin LA-treated subject (1/65, 1.5%) discontinued due to an
adverse event (depression).
In the single-blind titration period of this study,
subjects received Ritalin LA for up to 4 weeks. During this period a total of
six subjects (6/161, 3.7%) discontinued due to adverse events. The adverse
events leading to discontinuation were anger (in 2 patients), hypomania,
anxiety, depressed mood, fatigue, migraine and lethargy.
Adverse Events with Other Methylphenidate HCl Dosage
Forms
Nervousness and insomnia are the most common adverse
reactions reported with other methylphenidate products. In children, loss of
appetite, abdominal pain, weight loss during prolonged therapy, insomnia, and
tachycardia may occur more frequently; however, any of the other adverse
reactions listed below may also occur.
Other reactions include:
Cardiac: angina, arrhythmia, palpitations, pulse
increased or decreased, tachycardia
Gastrointestinal: abdominal pain, nausea
Immune: hypersensitivity reactions including skin
rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme
with histopathological findings of necrotizing vasculitis, and thrombocytopenic
purpura.
Metabolism/Nutrition: anorexia, weight loss during
prolonged therapy
Nervous System: dizziness, drowsiness, dyskinesia,
headache, rare reports of Tourette's syndrome, toxic psychosis
Vascular: blood pressure increased or decreased;
cerebrovascular vasculitis; cerebral occlusions; cerebral hemorrhages and
cerebrovascular accidents
Although a definite causal relationship has not been
established, the following have been reported in patients taking
methylphenidate:
Blood/Lymphatic: leukopenia and/or anemia
Hepatobiliary: abnormal liver function, ranging
from transaminase elevation to hepatic coma
Psychiatric: transient depressed mood, aggressive
behavior
Skin/Subcutaneous: scalp hair loss
Very rare reports of neuroleptic malignant syndrome (NMS)
have been received, and, in most of these, patients were concurrently receiving
therapies associated with NMS. In a single report, a ten-year-old boy who had
been taking methylphenidate for approximately 18 months experienced an NMS-like
event within 45 minutes of ingesting his first dose of venlafaxine. It is
uncertain whether this case represented a drug-drug interaction, a response to
either drug alone, or some other cause.
Drug Abuse And Dependence
Ritalin LA® (methylphenidate hydrochloride)
extended-release capsules, like other products containing methylphenidate, is a
Schedule II controlled substance. (See WARNINGS for boxed warning containing
drug abuse and dependence information.)
DRUG INTERACTIONS
Methylphenidate is metabolized primarily by
de-esterification (nonmicrosomal hydrolytic esterases) to ritalinic acid and
not through oxidative pathways.
The effects of gastrointestinal pH alterations on the
absorption of methylphenidate from Ritalin LA have not been studied. Since the
modified release characteristics of Ritalin LA are pH dependent, the
coadministration of antacids or acid suppressants could alter the release of
methylphenidate.
Methylphenidate may decrease the effectiveness of drugs
used to treat hypertension. Because of possible effects on blood pressure,
methylphenidate should be used cautiously with pressor agents.
As an inhibitor of dopamine reuptake, methylphenidate may
be associated with pharmacodynamic interactions when coadministered with direct
and indirect dopamine agonists (including DOPA and tricyclic antidepressants)
as well as dopamine antagonists (antipsychotics, e.g., haloperidol).
Case reports suggest a potential interaction of
methylphenidate with coumarin anticoagulants, anticonvulsants (e.g.,
phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine,
clomipramine, desipramine) but pharmacokinetic interactions were not confirmed
when explored at higher sample sizes. Downward dose adjustment of these drugs
may be required when given concomitantly with methylphenidate. It may be
necessary to adjust the dosage and monitor plasma drug concentrations (or, in
the case of coumarin, coagulation times), when initiating or discontinuing
concomitant methylphenidate.
Methylphenidate is not metabolized by cytochrome P450 to
a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not
expected to have any relevant impact on methylphenidate pharmacokinetics.
Conversely, the d- and l- enantiomers of methylphenidate did not relevantly
inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A.
Methylphenidate coadministration did not increase plasma
concentrations of the CYP2D6 substrate desipramine.
An interaction with the anticoagulant ethylbiscoumacetate
in 4 subjects was not confirmed in a subsequent study with a higher sample size
(n=12).
Other specific drug-drug interaction studies with
methylphenidate have not been performed in vivo.
