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
Topamax Warnings, Precautions, Pregnancy, Nursing, Abuse - Topiramate
Topamax Warnings, Precautions, Pregnancy, Nursing, Abuse - Topiramate
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 treatment although cases can occur at any time during treatment. Bicarbonate
decrements are usually mild-moderate (average decrease of 4 mEq/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 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.
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 1% 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 <17 mEq/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 <17 mEq/L and >5 mEq/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 > 5 mEq/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 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.
Acute Myopia and Secondary Angle Closure Glaucoma
A syndrome consisting of acute myopia associated with secondary
angle closure glaucoma has been reported in patients receiving TOPAMAX®.
Symptoms include acute onset of decreased visual acuity and/or ocular pain.
Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular
hyperemia (redness) and increased intraocular pressure. Mydriasis may or may
not be present. This syndrome may be associated with supraciliary effusion resulting
in anterior displacement of the lens and iris, with secondary angle closure
glaucoma. Symptoms typically occur within 1 month of initiating TOPAMAX®
therapy. In contrast to primary narrow angle glaucoma, which is rare under 40
years of age, secondary angle closure glaucoma associated with topiramate has
been reported in pediatric patients as well as adults. The primary treatment
to reverse symptoms is discontinuation of TOPAMAX® as rapidly
as possible, according to the judgement of the treating physician. Other measures,
in conjunction with discontinuation of TOPAMAX®, may be helpful.
Elevated intraocular pressure of any etiology, if left untreated,
can lead to serious sequelae including permanent vision loss.
Oligohidrosis and Hyperthermia
Oligohidrosis (decreased sweating), infrequently resulting
in hospitalization, has been reported in association with TOPAMAX®
use. Decreased sweating and an elevation in body temperature above normal characterized
these cases. Some of the cases were reported after exposure to elevated environmental
temperatures.
The majority of the reports have been in children. Patients,
especially pediatric patients, treated with TOPAMAX® should be
monitored closely for evidence of decreased sweating and increased body temperature,
especially in hot weather. Caution should be used when TOPAMAX®
is prescribed with other drugs that predispose patients to heat-related disorders;
these drugs include, but are not limited to, other carbonic anhydrase inhibitors
and drugs with anticholinergic activity.
Withdrawal of AEDs
Antiepileptic drugs, including TOPAMAX®, should
be withdrawn gradually to minimize the potential of increased seizure frequency.
Cognitive/Neuropsychiatric Adverse Events Adults
Adverse events most often associated with the use of TOPAMAX®
were central nervous system related. In adults, the most significant of these
can be classified into two general categories: 1) psychomotor slowing, difficulty
with concentration, and speech or language problems, in particular, word-finding
difficulties and 2) somnolence or fatigue. Additional nonspecific CNS effects
occasionally observed with topiramate as add-on therapy include dizziness or
imbalance, confusion, memory problems, and exacerbation of mood disturbances
(e.g., irritability and depression).
Reports of psychomotor slowing, speech and language problems,
and difficulty with concentration and attention were common in adults. Although
in some cases these events were mild to moderate, they at times led to withdrawal
from treatment. The incidence of psychomotor slowing is only marginally dose-related,
but both language problems and difficulty with concentration or attention clearly
increased in frequency with increasing dosage in the five double-blind trials
[see ADVERSE REACTIONS, Table 6].
Somnolence and fatigue were the most frequently reported adverse
events during clinical trials with TOPAMAX®. These events were
generally mild to moderate and occurred early in therapy. While the incidence
of somnolence does not appear to be dose-related, that of fatigue increases
at dosages above 400 mg/day.
Pediatric Patients
In double-blind clinical studies, the incidences of cognitive/neuropsychiatric
adverse events in pediatric patients were generally lower than previously observed
in adults. These events included psychomotor slowing, difficulty with concentration/attention,
speech disorders/related speech problems and language problems. The most frequently
reported neuropsychiatric events in this population were somnolence and fatigue.
No patients discontinued treatment due to adverse events in double-blind trials.
Sudden Unexplained Death in Epilepsy (SUDEP)
During the course of premarketing development of TOPAMAX®
(topiramate) Tablets, 10 sudden and unexplained deaths were recorded among a
cohort of treated patients (2,796 subject years of exposure). This represents
an incidence of 0.0035 deaths per patient year. Although this rate exceeds that
expected in a healthy population matched for age and sex, it is within the range
of estimates for the incidence of sudden unexplained deaths in patients with
epilepsy not receiving TOPAMAX® (ranging from 0.0005 for the
general population of patients with epilepsy, to 0.003 for a clinical trial
population similar to that in the TOPAMAX® program, to 0.005
for patients with refractory epilepsy).
PRECAUTIONS
General:
Kidney Stones
A total of 32/2,086 (1.5%) of adults exposed to topiramate
during its development reported the occurrence of kidney stones, an incidence
about 2-4 times greater than expected in a similar, untreated population. As
in the general population, the incidence of stone formation among topiramate
treated patients was higher in men. Kidney stones have also been reported in
pediatric patients.
An explanation for the association of TOPAMAX®
and kidney stones may lie in the fact that topiramate is a carbonic anhydrase
inhibitor. Carbonic anhydrase inhibitors, e.g., acetazolamide or dichlorphenamide,
promote stone formation by reducing urinary citrate excretion and by increasing
urinary pH. The concomitant use of TOPAMAX® with other carbonic
anhydrase inhibitors or potentially in patients on a ketogenic diet may create
a physiological environment that increases the risk of kidney stone formation,
and should therefore be avoided.
Increased fluid intake increases the urinary output, lowering
the concentration of substances involved in stone formation. Hydration is recommended
to reduce new stone formation.
Paresthesia
Paresthesia, an effect associated with the use of other carbonic
anhydrase inhibitors, appears to be a common effect of TOPAMAX®.
Adjustment of Dose in Renal Failure
The major route of elimination of unchanged topiramate and
its metabolites is via the kidney. Dosage adjustment may be required in patients
with reduced renal function (see DOSAGE AND ADMINISTRATION).
Decreased Hepatic Function
In hepatically impaired patients, topiramate should be administered
with caution as the clearance of topiramate may be decreased.
INFORMATION FOR PATIENTS
Patients taking TOPAMAX® should be told to seek
immediate medical attention if they experience blurred vision or periorbital
pain.
Patients, especially pediatric patients, treated with TOPAMAX®
should be monitored closely for evidence of decreased sweating and increased
body temperature, especially in hot weather.
Patients, particularly those with predisposing factors, should
be instructed to maintain an adequate fluid intake in order to minimize the
risk of renal stone formation [see PRECAUTIONS:
General, for support regarding hydration as a preventative measure].
Patients should be warned about the potential for somnolence,
dizziness, confusion, and difficulty concentrating and advised not to drive
or operate machinery until they have gained sufficient experience on topiramate
to gauge whether it adversely affects their mental and/or motor performance.
Additional food intake may be considered if the patient is
losing weight while on this medication.
Please refer to the end of the product labeling for important
information on how to take TOPAMAX (topiramate capsules) Sprinkle Capsules.
Laboratory Tests:
Measurement of baseline and periodic serum bicarbonate during
topiramate treatment is recommended. (see WARNINGS).
Carcinogenesis, Mutagenesis, Impairment of Fertility:
An increase in urinary bladder tumors was observed in mice
given topiramate (20, 75, and 300 mg/kg) in the diet for 21 months. The elevated
bladder tumor incidence, which was statistically significant in males and females
receiving 300 mg/kg, was primarily due to the increased occurrence of a smooth
muscle tumor considered histomorphologically unique to mice. Plasma exposures
in mice receiving 300 mg/kg were approximately 0.5 to 1 times steady-state exposures
measured in patients receiving topiramate monotherapy at the recommended human
dose (RHD) of 400 mg, and 1.5 to 2 times steady-state topiramate exposures in
patients receiving 400 mg of topiramate plus phenytoin. The relevance of this
finding to human carcinogenic risk is uncertain. No evidence of carcinogenicity
was seen in rats following oral administration of topiramate for 2 years at
doses up to 120 mg/kg (approximately 3 times the RHD on a mg/m2 basis).
Topiramate did not demonstrate genotoxic potential when tested
in a battery of in vitro and in vivo assays. Topiramate was not
mutagenic in the Ames test or the in vitro mouse lymphoma assay; it did
not increase unscheduled DNA synthesis in rat hepatocytes in vitro; and
it did not increase chromosomal aberrations in human lymphocytes in vitro
or in rat bone marrow in vivo.
No adverse effects on male or female fertility were observed
in rats at doses up to 100 mg/kg (2.5 times the RHD on a mg/m2 basis).
Pregnancy: Pregnancy Category C.
Topiramate has demonstrated selective developmental toxicity,
including teratogenicity, in experimental animal studies. When oral doses of
20, 100, or 500 mg/kg were administered to pregnant mice during the period of
organogenesis, the incidence of fetal malformations (primarily craniofacial
defects) was increased at all doses. The low dose is approximately 0.2 times
the recommended human dose (RHD=400 mg/day) on a mg/m2 basis. Fetal
body weights and skeletal ossification were reduced at 500 mg/kg in conjunction
with decreased maternal body weight gain.
In rat studies (oral doses of 20, 100, and 500 mg/kg or 0.2,
2.5, 30, and 400 mg/kg), the frequency of limb malformations (ectrodactyly,
micromelia, and amelia) was increased among the offspring of dams treated with
400 mg/kg (10 times the RHD on a mg/m2 basis) or greater during the
organogenesis period of pregnancy. Embryotoxicity (reduced fetal body weights,
increased incidence of structural variations) was observed at doses as low as
20 mg/kg (0.5 times the RHD on a mg/m2 basis). Clinical signs of
maternal toxicity were seen at 400 mg/kg and above, and maternal body weight
gain was reduced during treatment with 100 mg/kg or greater.
In rabbit studies (20, 60, and 180 mg/kg or 10, 35, and 120
mg/kg orally during organogenesis), embryo/fetal mortality was increased at
35 mg/kg (2 times the RHD on a mg/m2 basis) or greater, and teratogenic
effects (primarily rib and vertebral malformations) were observed at 120 mg/kg
(6 times the RHD on a mg/m2 basis). Evidence of maternal toxicity
(decreased body weight gain, clinical signs, and/or mortality) was seen at 35
mg/kg and above.
When female rats were treated during the latter part of gestation
and throughout lactation (0.2, 4, 20, and 100 mg/kg or 2, 20, and 200 mg/kg),
offspring exhibited decreased viability and delayed physical development at
200 mg/kg (5 times the RHD on a mg/m2 basis) and reductions in pre-
and/or postweaning body weight gain at 2 mg/kg (0.05 times the RHD on a mg/m2
basis) and above. Maternal toxicity (decreased body weight gain, clinical signs)
was evident at 100 mg/kg or greater.
In a rat embryo/fetal development study with a postnatal component
(0.2, 2.5, 30, or 400 mg/kg during organogenesis; noted above), pups exhibited
delayed physical development at 400 mg/kg (10 times the RHD on a mg/m2
basis) and persistent reductions in body weight gain at 30 mg/kg (1 times the
RHD on a mg/m2 basis) and higher.
There are no studies using TOPAMAX® in pregnant
women. TOPAMAX® should be used during pregnancy only if the potential
benefit outweighs the potential risk to the fetus.
In post-marketing experience, cases of hypospadias have been
reported in male infants exposed in utero to topiramate, with or without other
anticonvulsants; however, a causal relationship with topiramate has not been
established.
Labor and Delivery:
In studies of rats where dams were allowed to deliver pups
naturally, no drug-related effects on gestation length or parturition were observed
at dosage levels up to 200 mg/kg/day.
The effect of TOPAMAX® on labor and delivery
in humans is unknown.
Nursing Mothers:
Topiramate is excreted in the milk of lactating rats. The excretion
of topiramate in human milk has not been evaluated in controlled studies. Limited
observations in patients suggest an extensive secretion of topiramate into breast
milk. Since many drugs are excreted in human milk, and because the potential
for serious adverse reactions in nursing infants to TOPAMAX®
is unknown, the potential benefit to the mother should be weighed against the
potential risk to the infant when considering recommendations regarding nursing.
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).
Geriatric Use:
In clinical trials, 3% of patients were over 60. No age related
difference in effectiveness or adverse effects were evident. However, clinical
studies of topiramate did not include sufficient numbers of subjects aged 65
and over to determine whether they respond differently than younger subjects.
Dosage adjustment may be necessary for elderly patients with impaired renal
function (creatinine clearance rate £ 70 mL/min/1.73
m2) due to reduced clearance of topiramate. (See CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Race and Gender Effects:
Evaluation of effectiveness and safety in clinical trials has
shown no race or gender related effects.
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