A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Metadate Side Effects, and Drug Interactions - Methylphenidate Hydrochloride
Metadate Side Effects, and Drug Interactions - Methylphenidate Hydrochloride
SIDE EFFECTS
:
The premarketing development program for METADATE CD included
exposures in a total of 228 participants in clinical trials (188 pediatric patients
with ADHD, 40 healthy adult subjects). These participants received METADATE
CD 20, 40, and/or 60 mg/day. The 188 patients (ages 6 to 15) were evaluated
in one controlled clinical study, one controlled, crossover clinical study,
and one uncontrolled clinical study. Safety data on all patients are included
in the discussion that follows. Adverse reactions were assessed by collecting
adverse events, results of physical examinations, vital signs, weights, laboratory
analyses, and ECGs.
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, COSTART 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 Findings in Clinical Trials with METADATE CD:
Adverse Events Associated with Discontinuation of Treatment:
In the 3-week placebo-controlled, parallel-group trial, two
METADATE CD-treated patients (1%) and no placebo-treated patients discontinued
due to an adverse event (rash and pruritus; and headache, abdominal pain, and
dizziness, respectively).
Adverse Events Occurring at an Incidence of 5% or more Among
METADATE CD-Treated Patients:
Table 1 enumerates, for a pool of the three studies in pediatric
patients with ADHD, at METADATE CD doses of 20, 40, or 60 mg/day, the incidence
of treatment-emergent adverse events. One study was a 3-week placebo-controlled,
parallel-group trial, one study was a controlled, crossover trial, and the third
study was an open titration trial. The table includes only those events that
occurred in 5% or more of patients treated with METADATE CD where the incidence
in patients treated with METADATE CD was greater than the incidence in placebo-treated
patients.
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.
TABLE 1 : Incidence of Treatment-Emergent Events1
in a Pool of 3-4 Week Clinical Trials of METADATE CD
|
Body System
|
Preferred Term
|
METADATE CD (n=188)
|
Placebo (n=190)
|
|
General
|
Headache
|
12%
|
8%
|
| |
Abdominal pain (stomach ache)
|
7%
|
4%
|
|
Digestive System
|
Anorexia (loss of appetite)
|
9%
|
2%
|
|
Nervous System
|
Insomnia
|
5%
|
2%
|
1:Events, regardless of causality, for which the
incidence for patients treated with METADATE CD was at least 5% and greater
than the incidence among placebo-treated patients. Incidence has been rounded
to the nearest whole number.
Adverse Events with Other Methylphenidate HCl Products:
Nervousness and insomnia are the most common adverse reactions
reported with other methylphenidate products. Other reactions include hypersensitivity
(including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis,
erythema multiforme with histopathological findings of necrotizing vasculitis,
and thrombocytopenic purpura); anorexia; nausea; dizziness; palpitations; headache;
dyskinesia; drowsiness; blood pressure and pulse changes, both up and down;
tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss during
prolonged therapy. There have been rare reports of Tourette’s Syndrome. Toxic
psychosis has been reported. Although a definite causal relationship has not
been established, the following have been reported in patients taking this drug:
instances of abnormal liver function, ranging from transaminase elevation to
hepatic coma; isolated cases of cerebral arteritis and/or occlusion; leukopenia
and/or anemia; transient depressed mood; a few instances of scalp hair loss.
Very rare reports of neuroleptic malignant syndrome (NMS) have been reported,
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.
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 above may also occur.
DRUG ABUSE AND DEPENDENCE: Controlled Substance Class:
METADATE CD, like other methylphenidate products, is classified
as a Schedule II controlled substance by federal regulation.
Abuse, Dependence, and Tolerance:
See WARNINGS for boxed
warning containing drug abuse and dependence information.
DRUG INTERACTIONS
:
Because of possible effects on blood
pressure, METADATE CD should be used cautiously with pressor agents.
Human pharmacologic studies have shown that methylphenidate
may inhibit the metabolism of coumarin anticoagulants, anticonvulsants (e.g.,
phenobarbital, phenytoin, primidone), and some antidepressants (tricyclics and
selective serotonin reuptake inhibitors). 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.
Serious adverse events have been reported in concomitant use
with clonidine, although no causality for the combination has been established.
The safety of using methylphenidate in combination with clonidine or other centrally
acting alpha-2 agonists has not been systematically evaluated.
Carcinogenesis, Mutagenesis, and 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 30 times and 4 times the maximum recommended human
dose of METADATE CD on a mg/kg and mg/m2 basis, respectively. 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 increases 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 22 times and 5 times
the maximum recommended human dose of METADATE CD on a mg/kg and mg/m2
basis, respectively.
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 in 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 cells. Methylphenidate was negative in vivo in males and females in the
mouse bone marrow micronucleus assay.
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 up to 160 mg/kg/day, approximately 80-fold
and 8-fold the highest recommended human dose of METADATE CD on a mg/kg and
mg/m2 basis, respectively.
Pregnancy: Teratogenic Effects: Pregnancy Category C.
Methylphenidate has been shown to have teratogenic effects
in rabbits when given in doses of 200 mg/kg/day, which is approximately 100
times and 40 times the maximum recommended human dose on a mg/kg and mg/m2
basis, respectively.
A reproduction study in rats revealed no evidence of teratogenicity
at an oral dose of 58 mg/kg/day. However, this dose, which caused some maternal
toxicity, resulted in decreased postnatal pup weights and survival when given
to the dams from day one of gestation through the lactation period. This dose
is approximately 30 fold and 6 fold the maximum recommended human dose of METADATE
CD on a mg/kg and mg/m2 basis, respectively.
There are no adequate and well-controlled studies in pregnant
women. METADATE CD should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Nursing Mothers:
It is not known whether methylphenidate is excreted in human
milk. Because many drugs are excreted in human milk, caution should be exercised
if METADATE CD is administered to a nursing woman.
Pediatric Use:
The safety and efficacy of METADATE CD in children under 6
years old have not been established. Long-term effects of methylphenidate in
children have not been well established (see WARNINGS).
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