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From: Ortho
McNeil Re:
Topamax
12-2003
Important
Drug Warning
The
Prescribing information for Topamax (topiramate/topiramate capsules)
Tablets/Sprinkle Capsules has been revised to include a warning that
TOPAMAX causes hypercloremic, non-anion gap metabolic acidosis
(decreased serum bicarbonate). TOPAMAX is approved and marketed for
the adjunctive treatment of partial-onset seizures, generalized
tonic-clonic seizures associated with the Lennox-Gastaut syndrome in
adults and children two years of age and older.
Data on
hyperchloremic, non-anion gap metabolic acidosis are derived from
placebo-controlled trials and post-marketing experience in over 2.5
million patients. In clinical trials, the rate of occurrence of a
persistently decreased serum bicarbonate ranges from 23-67% for
patients treated with topiramate and 1-10% for placebo. The incidence
of markedly low serum bicarbonate in clinical trials ranges from
3-11% for topiramate and 1 to <1% for placebo.
Generally,
decreases in serum bicarbonate occur soon after initiation of
topiramate, although they can occur at any time during treatment.
Bicarbonate decrements are usually mild-moderate, with an average
decrease of 4mEQ/L at daily doses of 400 mg in adults and
approximately 6 mg/kg/day in pediatric patients. Rarely, patients can
experience decrements to values below 10 mEq/L.
Conditions or
therapies that predispose to acidosis (such as renal disease, severe
respiratory disorders, status epilepticus, diarrhea, surgery,
ketogenic diet, or drugs) may be additive to the bicarbonate lowering
effects of topiramate.
Some
manifestations of acute or chronic metabolic acidosis may include
hyperventilation, nonspecific symptoms such s fatigue and anorexia,
or more sever sequelae including cardiac arrhythmias or stupor.
Chronic, untreated metabolic acidosis may increase the risk for
nephrolithiasis or nephrocalcinosis, and may also result in
osteomalacia (referred to as rickets in pediatric patients) and/or
osteoporosis with an increased risk for fractures. Chronic metabolic
acidosis in pediatric patients may also reduce growth rates. A
reduction in growth rate may eventually decrease the maximal height
achieved. The effect of topiramate on growth and bone-related
sequelae has not been systematically investigated.
Measurement of
baseline and periodic serum bicarbonate during topiramate treatment
is recommended. If metabolic acidosis develops and persists,
consideration should be given to reducing the dose or discontinuing
topiramate (using dose tapering). If the decision is made to continue
patients on topiramate in the face of persistent acidosis, alkali
treatment should be considered.
The following
has been added to TOPAMAX prescribing information.
Under WARNINGS
Metabolic Acidosis
Hyperchloremic,
non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate
below the normal reference range in the absence of chronic
respiratory alkalosis) is associated with topiramate treatment. This
metabolic acidosis is caused by renal bicarbonate loss due to the
inhibitory effect of topiramate on carbonic anhydrase. Such
electrolyte imbalance has been observed with the use of topiramate in
placebo-controlled clinical trials and in the post-marketing period.
Generally, topiramate-induced metabolic acidosis occurs early in the
treatment although cases can occur at any time during treatment.
Bicarbonate decrements are usually mild-moderate (average decrease of
4mEq/L at daily doses of 400 mg in adults and at approximately 6
mg/kg/day in pediatric patients); rarely, patients can experience
severe decrements to values below 10mEq/L. Conditions or therapies
that predispose to acidosis (such as renal disease, severe
respiratory disorders, status epilepticus, diarrhea, surgery,
ketogenic diet, or drugs) may be additive to the bicarbonate lowering
effects of topiramate.
In adults, the
incidence of persistent treatment-emergent decreases in serum
bicarbonate (levels of <20 mEq/L at two consecutive visits or at
the final visit) in controlled clinical trials for adjunctive
treatment of epilepsy was 32% for 400 mg/day, and !% for placebo.
Metabolic acidosis has been observed at doses as low as 50 mg/day.
The incidence of a markedly abnormally low serum bicarbonate (i.e.,
absolute value <17mEq/L and >5 mEq/L decrease from
pretreatment) in these trials was 3% for 400 mg/day, and 0% for
placebo. Serum bicarbonate levels have not been systematically
evaluated at daily doses greater than 400 mg/day.
In pediatric
patients (<16 years of age), the incidence of persistent
treatment-emergent decreases in serum bicarbonate in
placebo-controlled trials for adjunctive treatment of Lennox-Gastaut
Syndrome or refractory partial onset seizures was 67% for TOPAMAX (at
approximately 6 mg/kg/day), and 10% for placebo. The incidence of a
markedly abnormally low serum bicarbonate (i.e., absolute value
<17mEq/L and >5mEq/L decrease from pretreatment) in these
trials was 11% for TOPAMAX and 0% for placebo. Cases of moderately
severe metabolic acidosis have been reported in patients as young as
5 months old, especially at daily doses above 5 mg/kg/day.
Although not
approved for the prophylaxis of migraine, the incidence of persistent
treatment-emergent decreases in serum bicarbonate in
placebo-controlled trials for adults for prophylaxis of migraine was
44% for 200 mg/day, 39% for 100 mg/day, 23% for 50 mg/day, and 7% for
placebo. The incidence of a markedly abnormally low serum bicarbonate
(i.e., absolute value<17 mEq/L and >5mEq/L decrease from
pretreatment) in these trials was 11% for 200 mg/day, 9% for 100
mg/day, 2% for 50 mg/day, and 1% for placebo.
Some
manifestations of acute or chronic metabolic acidosis may include
hyperventilation, nonspecific symptoms such as fatigue and anorexia,
or more severe sequelae including cardiac arrhythmias or stupor.
Chronic, untreated metabolic acidosis may increase the risk for
nephrolithiasis or nephrocalcinosis, and may also result in
osteomalacia (referred to as Rickets in pediatric patients) and / or
osteoporosis with an increased risk for fractures. Chronic metabolic
acidosis in pediatric patients may also reduce growth rates. A
reduction in growth rates may eventually decrease the maximal height
achieved. The effect of topiramate on growth and bone related
sequelae has not been systematically investigated.
Measurement of
baseline and periodic serum bicarbonate during topiramate treatment
is recommended. If metabolic acidosis develops and persists,
consideration should be given to reducing the dose or discontinuing
topiramate (using dose tapering). If the decision is made to continue
patients on topiramate in the face or persistent acidosis, alkali
treatment should be considered.
Under Precautions:
Laboratory Tests
Measurement of
baseline and periodic serum bicarbonate during topiramate treatment
is recommended ( see WARNINGS).
Pediatric Use:
Safety and
effectiveness in patients below the age of 2 years have not been
established. Topiramate is associated with metabolic acidosis.
Chronic untreated metabolic acidosis in pediatric patients may cause
osteomalacia (rickets) and may reduce growth rates. A reduction
in growth rate may eventually decrease the maximal height achieved.
The effect of topiramate on growth and bone-related sequelae has not
been systematically investigated (see Warnings).
Under OVERDOSE:
Topiramate
overdose has resulted in severe metabolic acidosis (see WARNINGS).
You can
further our understanding of adverse events by reporting all cases to
Ortho-McNeil at the contact numbers listed below or to the FDA
MedWatch Program by phone (1-800 FDA 1088), by fax (1-800-FDA-0178,
by mail (using postage paid form to MedWatch, FDA, 5600 Fishers Lane,
Rockville, MD 20852-9787) or via www.accessdata.fda.gov/scripts//medwatch/.
A copy of the
full Prescribing Information is enclosed for your reference. If you
have any questions regarding TOPOMAX tablets and TOPOMAX Sprinkle
Caplets, please feel free to call Ortho-McNeil Medical Affairs
Division at 1-800-682-6532
Sincerely,
Joseph
Hulihan, MD
Group
Director, CNS Research
Ortho-McNeil
Pharmaceutical,
Inc. 1000 Route 202, PO Box 300 Raritan, NJ
08869-0602 908-218-6000 Telephone |
