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 Side Effects, and Drug Interactions - Topiramate
Topamax Side Effects, and Drug Interactions - Topiramate
SIDE EFFECTS
The data described in the following section were obtained using
TOPAMAX (topiramate) Tablets.
The most commonly observed adverse events associated with the
use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults
with partial onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut
syndrome, that were seen at greater frequency in topiramate-treated patients
and did not appear to be dose-related were: somnolence, dizziness, ataxia, speech
disorders and related speech problems, psychomotor slowing, abnormal vision,
difficulty with memory, paresthesia and diplopia [see Table 4]. The most common
dose-related adverse events at dosages of 200 to 1,000 mg/day were: fatigue,
nervousness, difficulty with concentration or attention, confusion, depression,
anorexia, language problems, anxiety, mood problems, and weight decrease [see
Table 6].
Adverse events associated with the use of topiramate at dosages
of 5 to 9 mg/kg/day in controlled trials in pediatric patients with partial
onset seizures, primary generalized tonic-clonic seizures, or Lennox-Gastaut
syndrome, that were seen at greater frequency in topiramate-treated patients
were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention,
difficulty with memory, aggressive reaction, and weight decrease [see Table
7].
In controlled clinical trials in adults, 11% of patients receiving
topiramate 200 to 400 mg/day as adjunctive therapy discontinued due to adverse
events. This rate appeared to increase at dosages above 400 mg/day. Adverse
events associated with discontinuing therapy included somnolence, dizziness,
anxiety, difficulty with concentration or attention, fatigue, and paresthesia
and increased at dosages above 400 mg/day. None of the pediatric patients who
received topiramate adjunctive therapy at 5 to 9 mg/kg/day in controlled clinical
trials discontinued due to adverse events.
Approximately 28% of the 1,757 adults with epilepsy who received
topiramate at dosages of 200 to 1,600 mg/day in clinical studies discontinued
treatment because of adverse events; an individual patient could have reported
more than one adverse event. These adverse events were: psychomotor slowing
(4.0%), difficulty with memory (3.2%), fatigue (3.2%), confusion (3.1%), somnolence
(3.2%), difficulty with concentration/attention (2.9%), anorexia (2.7%), depression
(2.6%), dizziness (2.5%), weight decrease (2.5%), nervousness (2.3%), ataxia
(2.1%), and paresthesia (2.0%). Approximately 11% of the 310 pediatric patients
who received topiramate at dosages up to 30 mg/kg/day discontinued due to adverse
events. Adverse events associated with discontinuing therapy included aggravated
convulsions (2.3%), difficulty with concentration/attention (1.6%), language
problems (1.3%), personality disorder (1.3%), and somnolence (1.3%).
Incidence in Controlled Clinical Trials – Add-On Therapy –
Partial Onset Seizures, Primary Generalized Tonic-Clonic Seizures, and Lennox-Gastaut
Syndrome
Table 4 lists treatment-emergent adverse events that occurred
in at least 1% of adults treated with 200 to 400 mg/day topiramate in controlled
trials that were numerically more common at this dose than in the patients treated
with placebo. In general, most patients who experienced adverse events during
the first eight weeks of these trials no longer experienced them by their last
visit. Table 7 lists treatment-emergent adverse events that occurred in at least
1% of pediatric patients treated with 5 to 9 mg/kg topiramate in controlled
trials that were numerically more common than in patients treated with placebo.
The prescriber should be aware that these data were obtained
when TOPAMAX® was added to concurrent antiepileptic drug therapy
and cannot be used to predict the frequency of adverse events in the course
of usual medical practice where patient characteristics and other factors may
differ from those prevailing during clinical studies. Similarly, the cited frequencies
cannot be directly compared with data obtained from other clinical investigations
involving different treatments, uses, or investigators. Inspection of these
frequencies, however, does provide the prescribing physician with a basis to
estimate the relative contribution of drug and non-drug factors to the adverse
event incidences in the population studied.
|
Table 4: Incidence of Treatment-Emergent Adverse
Events in Placebo-Controlled, Add-On Trials in Adultsa,b Where
Rate Was > 1% in Any Topiramate Group and Greater Than the Rate in
Placebo-Treated Patients
|
| |
TOPAMAX Dosage (mg/day)
|
|
Body System/
|
Placebo
|
200-400
|
600-1,000
|
|
Adverse Eventc
|
(N=291)
|
(N=183)
|
(N=414)
|
|
Body as a Whole-General Disorders
|
|
|
|
|
Fatigue
|
13
|
15
|
30
|
|
Asthenia
|
1
|
6
|
3
|
|
Back Pain
|
4
|
5
|
3
|
|
Chest Pain
|
3
|
4
|
2
|
|
Influenza-Like Symptoms
|
2
|
3
|
4
|
|
Leg Pain
|
2
|
2
|
4
|
|
Hot Flushes
|
1
|
2
|
1
|
|
Allergy
|
1
|
2
|
3
|
|
Edema
|
1
|
2
|
1
|
|
Body Odor
|
0
|
1
|
0
|
|
Rigors
|
0
|
1
|
<1
|
|
Central & Peripheral Nervous System Disorders
|
|
Dizziness
|
15
|
25
|
32
|
|
Ataxia
|
7
|
16
|
14
|
|
Speech Disorders/Related Speech Problems
|
2
|
13
|
11
|
|
Paresthesia
|
4
|
11
|
19
|
|
Nystagmus
|
7
|
10
|
11
|
|
Tremor
|
6
|
9
|
9
|
|
Language Problems
|
1
|
6
|
10
|
|
Coordination Abnormal
|
2
|
4
|
4
|
|
Hypoaesthesia
|
1
|
2
|
1
|
|
Gait Abnormal
|
1
|
3
|
2
|
|
Muscle Contractions Involuntary
|
1
|
2
|
2
|
|
Stupor
|
0
|
2
|
1
|
|
Vertigo
|
1
|
1
|
2
|
|
Gastro-Intestinal System Disorders
|
|
Nausea
|
8
|
10
|
12
|
|
Dyspepsia
|
6
|
7
|
6
|
|
Abdominal Pain
|
4
|
6
|
7
|
|
Constipation
|
2
|
4
|
3
|
|
Gastroenteritis
|
1
|
2
|
1
|
|
Dry Mouth
|
1
|
2
|
4
|
|
Gingivitis
|
<1
|
1
|
1
|
|
GI Disorder
|
<1
|
1
|
0
|
|
Hearing and Vestibular Disorders
|
|
Hearing Decreased
|
1
|
2
|
1
|
|
Metabolic and Nutritional Disorders
|
|
Weight Decrease
|
3
|
9
|
13
|
|
Muscle-Skeletal System Disorders
|
|
Myalgia
|
1
|
2
|
2
|
|
Skeletal Pain
|
0
|
1
|
0
|
|
Platelet, Bleeding, & Clotting Disorders
|
|
Epistaxis
|
1
|
2
|
1
|
|
Psychiatric Disorders
|
|
Somnolence
|
12
|
29
|
28
|
|
Nervousness
|
6
|
16
|
19
|
|
Psychomotor Slowing
|
2
|
13
|
21
|
|
Difficulty with Memory
|
3
|
12
|
14
|
|
Anorexia
|
4
|
10
|
12
|
|
Confusion
|
5
|
11
|
14
|
|
Depression
|
5
|
5
|
13
|
|
Difficulty with Concentration/Attention
|
2
|
6
|
14
|
|
Mood Problems
|
2
|
4
|
9
|
|
Agitation
|
2
|
3
|
3
|
|
Aggressive Reaction
|
2
|
3
|
3
|
|
Emotional Lability
|
1
|
3
|
3
|
|
Cognitive Problems
|
1
|
3
|
3
|
|
Libido Decreased
|
1
|
2
|
<1
|
|
Apathy
|
1
|
1
|
3
|
|
Depersonalization
|
1
|
1
|
2
|
|
Table 4: Incidence of Treatment-Emergent Adverse
Events in Placebo-Controlled, Add-On Trials in Adultsa,b Where
Rate Was > 1% in Any Topiramate Group and Greater Than the Rate in
Placebo-Treated Patients (Continued)
|
| |
TOPAMAX Dosage (mg/day)
|
|
Body System/
|
Placebo
|
200-400
|
600-1,000
|
|
Adverse Eventc
|
(N=291)
|
(N=183)
|
(N=414)
|
|
Reproductive Disorders, Female
|
|
Breast Pain
|
2
|
4
|
0
|
|
Amenorrhea
|
1
|
2
|
2
|
|
Menorrhagia
|
0
|
2
|
1
|
|
Menstrual Disorder
|
1
|
2
|
1
|
|
Reproductive Disorders, Male
|
|
Prostatic Disorder
|
<1
|
2
|
0
|
|
Resistance Mechanism Disorders
|
|
|
|
|
Infection
|
1
|
2
|
1
|
|
Infection Viral
|
1
|
2
|
<1
|
|
Moniliasis
|
<1
|
1
|
0
|
|
Respiratory System Disorders
|
|
Pharyngitis
|
2
|
6
|
3
|
|
Rhinitis
|
6
|
7
|
6
|
|
Sinusitis
|
4
|
5
|
6
|
|
Dyspnea
|
1
|
1
|
2
|
|
Skin and Appendages Disorders
|
|
Skin Disorder
|
<1
|
2
|
1
|
|
Sweating Increased
|
<1
|
1
|
<1
|
|
Rash Erythematous
|
<1
|
1
|
<1
|
|
Special Sense Other, Disorders
|
|
Taste Perversion
|
0
|
2
|
4
|
|
Urinary System Disorders
|
|
Hematuria
|
1
|
2
|
<1
|
|
Urinary Tract Infection
|
1
|
2
|
3
|
|
Micturition Frequency
|
1
|
1
|
2
|
|
Urinary Incontinence
|
<1
|
2
|
1
|
|
Urine Abnormal
|
0
|
1
|
<1
|
|
Vision Disorders
|
|
Vision Abnormal
|
2
|
13
|
10
|
|
Diplopia
|
5
|
10
|
10
|
|
White Cell and RES Disorders
|
|
Leukopenia
|
1
|
2
|
1
|
|
a Patients in these add-on trials were receiving
1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX®
or placebo.
|
|
b Values represent the percentage of patients
reporting a given adverse event. Patients may have reported more than
one adverse event during the study and can be included in more than one
adverse event category.
|
|
c Adverse events reported by at least 1% of
patients in the TOPAMAX® 200-400 mg/day group and more
common than in the placebo group are listed in this table.
|
Incidence in Study 119 – Add-On Therapy– Adults with Partial
Onset Seizures
Study 119 was a randomized, double-blind, placebo-controlled,
parallel group study with 3 treatment arms: 1) placebo; 2) topiramate 200 mg/day
with a 25 mg/day starting dose, increased by 25 mg/day each week for 8 weeks
until the 200 mg/day maintenance dose was reached; and 3) topiramate 200 mg/day
with a 50 mg/day starting dose, increased by 50 mg/day each week for 4 weeks
until the 200 mg/day maintenance dose was reached. All patients were maintained
on concomitant carbamazepine with or without another concomitant antiepileptic
drug.
The incidence of adverse events did not differ significantly
between the 2 topiramate regimens. The cited frequencies of adverse events cannot
be directly compared with data obtained in other studies using different patients
with different titration rates and taking different combinations of concomitant
medications.
|
Table 5: Incidence of Treatment-Emergent Adverse
Events in Study 119a,b Where Rate Was > 2% in the Topiramate
Group and Greater Than the Rate in Placebo-Treated Patients
|
| |
TOPAMAX Dosage (mg/day)
|
|
Body System/
|
Placebo
|
200
|
|
Adverse Eventc
|
(N=92)
|
(N=171)
|
|
Body as a Whole-General Disorders
|
| |
Fatigue
|
4
|
9
|
| |
Chest Pain
|
1
|
2
|
|
Cardiovascular Disorders, General
|
| |
Hypertension
|
0
|
2
|
|
Central & Peripheral Nervous System Disorders
|
| |
Paresthesia
|
2
|
9
|
| |
Dizziness
|
4
|
7
|
| |
Tremor
|
2
|
3
|
| |
Hypoasthesia
|
0
|
2
|
| |
Leg Cramps
|
0
|
2
|
| |
Language Problems
|
0
|
2
|
|
Gastro-Intestinal System Disorders
|
| |
Abdominal Pain
|
3
|
5
|
| |
Constipation
|
0
|
4
|
| |
Diarrhea
|
1
|
2
|
| |
Dyspepsia
|
0
|
2
|
| |
Dry Mouth
|
0
|
2
|
|
Hearing and Vestibular Disorders
|
| |
Tinnitus
|
0
|
2
|
|
Metabolic and Nutritional Disorders
|
| |
Weight Decrease
|
4
|
8
|
|
Psychiatric Disorders
|
| |
Somnolence
|
9
|
15
|
| |
Anorexia
|
7
|
9
|
| |
Nervousness
|
2
|
9
|
| |
Difficulty with Concentration/Attention
|
0
|
5
|
| |
Insomnia
|
3
|
4
|
| |
Difficulty with Memory
|
1
|
2
|
| |
Aggressive Reaction
|
0
|
2
|
|
Respiratory System Disorders
|
| |
Rhinitis
|
0
|
4
|
|
Urinary System Disorders
|
| |
Cystitis
|
0
|
2
|
|
Vision Disorders
|
| |
Diplopia
|
0
|
2
|
| |
Vision Abnormal
|
0
|
2
|
|
a Patients in these add-on trials were receiving
1 to 2 concomitant antiepileptic drugs in addition to TOPAMAX®
or placebo.
|
|
b Values represent the percentage of patients
reporting a given adverse event. Patients may have reported more than
one adverse event during the study and can be included in more than one
adverse event category.
|
|
c Adverse events reported by at least 2% of
patients in the TOPAMAX® 200 mg/day group and more common
than in the
placebo group are listed in this table.
|
|
Table 6: Incidence (%) of Dose-Related Adverse
Events From Placebo-Controlled, Add-On Trials in Adults with Partial Onset
Seizuresa
|
| |
TOPAMAX® Dosage (mg/day)
|
| |
Placebo
|
200
|
400
|
600 - 1,000
|
|
Adverse Event
|
(N =216)
|
(N = 45)
|
(N = 68)
|
(N = 414 )
|
|
Fatigue
|
13
|
11
|
12
|
30
|
|
Nervousness
|
7
|
13
|
18
|
19
|
|
Difficulty with Concentration/Attention
|
1
|
7
|
9
|
14
|
|
Confusion
|
4
|
9
|
10
|
14
|
|
Depression
|
6
|
9
|
7
|
13
|
|
Anorexia
|
4
|
4
|
6
|
12
|
|
Language problems
|
<1
|
2
|
9
|
10
|
|
Anxiety
|
6
|
2
|
3
|
10
|
|
Mood problems
|
2
|
0
|
6
|
9
|
|
Weight decrease
|
3
|
4
|
9
|
13
|
|
a Dose-response studies were not conducted
for other adult indications or for pediatric indications.
|
|
Table 7: Incidence (%) of Treatment-Emergent Adverse
Events in Placebo-Controlled, Add-On Trials in Pediatric Patients Ages
2 -16 Yearsa,b (Events that Occurred in at Least 1% of Topiramate-Treated
Patients and Occurred More Frequently in Topiramate-Treated Than Placebo-Treated
Patients)
|
|
Body System/
|
Placebo
|
Topiramate
|
|
Adverse Event
|
(N=101)
|
(N=98)
|
|
Body as a Whole - General Disorders
|
|
Fatigue
|
5
|
16
|
|
Injury
|
13
|
14
|
|
Allergic Reaction
|
1
|
2
|
|
Back Pain
|
0
|
1
|
|
Pallor
|
0
|
1
|
|
Cardiovascular Disorders, General
|
|
Hypertension
|
0
|
1
|
|
Central & Peripheral Nervous System Disorders
|
|
|
|
Gait Abnormal
|
5
|
8
|
|
Ataxia
|
2
|
6
|
|
Hyperkinesia
|
4
|
5
|
|
Dizziness
|
2
|
4
|
|
Speech Disorders/Related Speech Problems
|
2
|
4
|
|
Hyporeflexia
|
0
|
2
|
|
Convulsions Grand Mal
|
0
|
1
|
|
Fecal Incontinence
|
0
|
1
|
|
Paresthesia
|
0
|
1
|
|
Gastro-Intestinal System Disorders
|
|
Nausea
|
5
|
6
|
|
Saliva Increased
|
4
|
6
|
|
Constipation
|
4
|
5
|
|
Gastroenteritis
|
2
|
3
|
|
Dysphagia
|
0
|
1
|
|
Flatulence
|
0
|
1
|
|
Gastroesophageal Reflux
|
0
|
1
|
|
Glossitis
|
0
|
1
|
|
Gum Hyperplasia
|
0
|
1
|
|
Heart Rate and Rhythm Disorders
|
|
Bradycardia
|
0
|
1
|
|
Metabolic and Nutritional Disorders
|
|
Weight Decrease
|
1
|
9
|
|
Thirst
|
1
|
2
|
|
Hypoglycemia
|
0
|
1
|
|
Weight Increase
|
0
|
1
|
|
Platelet, Bleeding, & Clotting Disorders
|
|
Purpura
|
4
|
8
|
|
Epistaxis
|
1
|
4
|
|
Hematoma
|
0
|
1
|
|
Prothrombin Increased
|
0
|
1
|
|
Thrombocytopenia
|
0
|
1
|
|
Psychiatric Disorders
|
|
Somnolence
|
16
|
26
|
|
Anorexia
|
15
|
24
|
|
Nervousness
|
7
|
14
|
|
Personality Disorder (Behavior Problems)
|
9
|
11
|
|
Difficulty with Concentration/Attention
|
2
|
10
|
|
Aggressive Reaction
|
4
|
9
|
|
Insomnia
|
7
|
8
|
|
Difficulty with Memory NOS
|
0
|
5
|
|
Confusion
|
3
|
4
|
|
Psychomotor Slowing
|
2
|
3
|
|
Appetite Increased
|
0
|
1
|
|
Neurosis
|
0
|
1
|
|
Reproductive Disorders, Female
|
| |
Leukorrhoea
|
0
|
2
|
|
Resistance Mechanism Disorders
|
| |
Infection Viral
|
3
|
7
|
|
Respiratory System Disorders
|
| |
Pneumonia
|
1
|
5
|
| |
Respiratory Disorder
|
0
|
1
|
|
Skin and Appendages Disorders
|
| |
Skin Disorder
|
2
|
3
|
| |
Alopecia
|
1
|
2
|
| |
Dermatitis
|
0
|
2
|
| |
Hypertrichosis
|
1
|
2
|
| |
Rash Erythematous
|
0
|
2
|
| |
Eczema
|
0
|
1
|
| |
Seborrhoea
|
0
|
1
|
| |
Skin Discoloration
|
0
|
1
|
|
Urinary System Disorders
|
| |
Urinary Incontinence
|
2
|
4
|
| |
Nocturia
|
0
|
1
|
|
Vision Disorders
|
| |
Eye Abnormality
|
1
|
2
|
| |
Vision Abnormal
|
1
|
2
|
| |
Diplopia
|
0
|
1
|
| |
Lacrimation Abnormal
|
0
|
1
|
| |
Myopia
|
0
|
1
|
|
White Cell and RES Disorders
|
| |
Leukopenia
|
0
|
2
|
|
a Patients in these add-on trials were receiving 1 to
2 concomitant antiepileptic drugs in addition to TOPAMAX®
or placebo.
|
|
b Values represent the percentage of patients reporting
a given adverse event. Patients may have reported more than one adverse
event during the study and can be included in more than one adverse event
category.
|
Other Adverse Events Observed
Other events that occurred in more than 1% of adults treated
with 200 to 400 mg of topiramate in placebo-controlled trials but with equal
or greater frequency in the placebo group were: headache, injury, anxiety, rash,
pain, convulsions aggravated, coughing, fever, diarrhea, vomiting, muscle weakness,
insomnia, personality disorder, dysmenorrhea, upper respiratory tract infection,
and eye pain.
Other Adverse Events Observed During All Clinical Trials
Topiramate, initiated as adjunctive therapy, has been administered
to 1927 adults and 313 pediatric patients with epilepsy during all clinical
studies. During these studies, all adverse events were recorded by the clinical
investigators using terminology of their own choosing. To provide a meaningful
estimate of the proportion of individuals having adverse events, similar types
of events were grouped into a smaller number of standardized categories using
modified WHOART dictionary terminology. The frequencies presented represent
the proportion of patients who experienced an event of the type cited on at
least one occasion while receiving topiramate. Reported events are included
except those already listed in the previous table or text, those too general
to be informative, and those not reasonably associated with the use of the drug.
Events are classified within body system categories and enumerated
in order of decreasing frequency using the following definitions: frequent
occurring in at least 1/100 patients; infrequent occurring in 1/100 to
1/1000 patients; rare occurring in fewer than 1/1000 patients.
Autonomic Nervous System Disorders: Infrequent:
vasodilation.
Body as a Whole: Infrequent: syncope, abdomen
enlarged. Rare: alcohol intolerance.
Cardiovascular Disorders, General: Infrequent:
hypotension, postural hypotension.
Central & Peripheral Nervous System Disorders: Frequent:
hypertonia.
Infrequent: neuropathy, apraxia, hyperaesthesia, dyskinesia,
dysphonia, scotoma, ptosis, dystonia, visual field defect, encephalopathy, EEG
abnormal. Rare: upper motor neuron lesion, cerebellar syndrome, tongue
paralysis.
Gastrointestinal System Disorders: Frequent:
diarrhea, vomiting. Infrequent: hemorrhoids, stomatitis, melena, gastritis,
tongue edema, esophagitis.
Heart Rate and Rhythm Disorders: Infrequent:
AV block.
Liver and Biliary System Disorders: Infrequent:
SGPT increased, SGOT increased, gamma-GT increased.
Metabolic and Nutritional Disorders: Frequent:
dehydration. Infrequent: hypokalemia, alkaline phosphatase increased,
hypocalcemia, hyperlipemia, acidosis, hyperglycemia, xerophthalmia. Rare:
hyperchloremia, diabetes mellitus, hypernatremia, hyponatremia, hypocholesterolemia,
hypophosphatemia, creatinine increased.
Musculoskeletal System Disorders: Frequent: arthralgia.
Infrequent: arthrosis.
Myo-, Endo-, Pericardial & Valve Disorders: Infrequent:
angina pectoris.
Neoplasms: Infrequent: thrombocythemia. Rare:
polycythemia.
Platelet, Bleeding, and Clotting Disorders: Infrequent:
gingival bleeding. Rare: pulmonary embolism.
Psychiatric Disorders: Frequent: impotence, hallucination,
euphoria, psychosis, suicide attempt. Infrequent: paranoid reaction,
delusion, paranoia, delirium, abnormal dreaming, neurosis, Rare: libido
increased, manic reaction.
Red Blood Cell Disorders: Frequent: anemia. Rare:
marrow depression, pancytopenia.
Reproductive Disorders, Male: Infrequent: ejaculation
disorder, breast discharge.
Skin and Appendages Disorders: Frequent: acne.
Infrequent: urticaria, photosensitivity reaction, abnormal hair texture.
Rare: chloasma.
Special Senses Other, Disorders: Infrequent:
taste loss, parosmia.
Urinary System Disorders: Frequent: dysuria,
renal calculus. Infrequent: urinary retention, face edema, renal pain,
albuminuria, polyuria, oliguria.
Vascular (Extracardiac) Disorders: Infrequent:
flushing, deep vein thrombosis, phlebitis. Rare: vasospasm.
Vision Disorders: Frequent: conjunctivitis. Infrequent:
abnormal accommodation, photophobia, strabismus. Rare: mydriasis, iritis.
White Cell and Reticuloendothelial System Disorders:
Infrequent: lymphadenopathy, eosinophilia, lymphopenia, granulocytopenia.
Rare: lymphocytosis.
Postmarketing and Other Experience
In addition to the adverse experiences reported during clinical
testing of TOPAMAX®, the following adverse experiences have been
reported worldwide in patients receiving topiramate post-approval. These adverse
experiences have not been listed above and data are insufficient to support
an estimate of their incidence or to establish causation. The listing is alphabetized:
bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis), hepatic failure (including fatalities), hepatitis,
pancreatitis, pemphigus, and renal tubular acidosis.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of TOPAMAX®
has not been evaluated in human studies.
DRUG INTERACTIONS
Antiepileptic Drugs
Potential interactions between topiramate and standard AEDs
were assessed in controlled clinical pharmacokinetic studies in patients with
epilepsy. The effects of these interactions on mean plasma AUCs are summarized
in the following table:
In Table 3, the second column (AED concentration) describes
what happens to the concentration of the AED listed in the first column when
topiramate is added.
The third column (topiramate concentration) describes how the
coadministration of a drug listed in the first column modifies the concentration
of topiramate in experimental settings when TOPAMAX® was given
alone.
|
Table 3: Summary of AED Interactions with TOPAMAX®
|
|
AED
|
AED
|
Topiramate
|
|
Co-administered
|
Concentration
|
Concentration
|
|
Phenytoin
|
NC or 25% increasea
|
48% decrease
|
|
Carbamazepine (CBZ)
|
NC
|
40% decrease
|
|
CBZ epoxideb
|
NC
|
NE
|
|
Valproic acid
|
11% decrease
|
14% decrease
|
|
Phenobarbital
|
NC
|
NE
|
|
Primidone
|
NC
|
NE
|
|
a = Plasma concentration increased 25% in
some patients, generally those on a b.i.d. dosing regimen of phenytoin.
|
|
b = Is not administered but is an active metabolite
of carbamazepine.
|
|
NC = Less than 10% change in plasma concentration.
|
|
AED = Antiepileptic drug.
|
|
NE = Not Evaluated.
|
Other Drug Interactions
Digoxin: In a single-dose study, serum digoxin AUC was
decreased by 12% with concomitant TOPAMAX® administration. The
clinical relevance of this observation has not been established.
CNS Depressants: Concomitant administration of TOPAMAX®
and alcohol or other CNS depressant drugs has not been evaluated in clinical
studies. Because of the potential of topiramate to cause CNS depression, as
well as other cognitive and/or neuropsychiatric adverse events, topiramate should
be used with extreme caution if used in combination with alcohol and other CNS
depressants.
Oral Contraceptives: In a pharmacokinetic interaction
study in healthy volunteers with a concomitantly administered combination oral
contraceptive product containing 1 mg norethindrone (NET) plus 35 mcg ethinyl
estradiol (EE), TOPAMAX® given in the absence of other medications
at doses of 50 to 200 mg/day was not associated with statistically significant
changes in mean exposure (AUC) to either component of the oral contraceptive.
In another study, exposure to EE was statistically significantly decreased at
doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given
as adjunctive therapy in patients taking valproic acid. In both studies, TOPAMAX®
(50 mg/day to 800 mg/day) did not significantly affect exposure to NET. Although
there was a dose dependent decrease in EE exposure for doses between 200-800
mg/day, there was no significant dose dependent change in EE exposure for doses
of 50-200 mg/day. The clinical significance of the changes observed is not known.
The possibility of decreased contraceptive efficacy and increased breakthrough
bleeding should be considered in patients taking combination oral contraceptive
products with TOPAMAX®. Patients taking estrogen containing contraceptives
should be asked to report any change in their bleeding patterns. Contraceptive
efficacy can be decreased even in the absence of breakthrough bleeding.
Others: Concomitant use of TOPAMAX®,
a weak carbonic anhydrase inhibitor, with other carbonic anhydrase inhibitors,
e.g., acetazolamide or dichlorphenamide, may create a physiological environment
that increases the risk of renal stone formation, and should therefore be avoided.
Drug/Laboratory Test Interactions: There are no known
interactions of topiramate with commonly used laboratory tests.
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