Pronunciation: toe-PIR-a-mate
Class: Anticonvulsant

Trade Names

Topamax
- Capsules, sprinkle 15 mg
- Capsules, sprinkle 25 mg
- Tablets 25 mg
- Tablets 50 mg
- Tablets 100 mg
- Tablets 200 mg

Topiragen
- Tablets 25 mg
- Tablets 50 mg
- Tablets 100 mg
- Tablets 200 mg

Apo-Topiramate (Canada)
CO Topiramate (Canada)
Gen-Topiramate (Canada)
PMS-Topiramate (Canada)
ratio-Topiramate (Canada)
Sandoz Topiramate (Canada)

Pharmacology

Precise mechanism is unknown, but topiramate may block repetitively elicited action potentials, affect ability of chloride ion to move into neurons, and antagonize an excitatory amino acid receptor.

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Pharmacokinetics

Absorption

Topiramate absorption is rapid. T _max is 2 h. Bioavailability is about 80% and is not affected by food. Steady state is reached in about 4 days.

Distribution

Topiramate is 15% to 41% bound to plasma proteins.

Metabolism

Topiramate is not extensively metabolized.

Elimination

Topiramate is primarily eliminated unchanged in urine (about 70% of a dose). Plasma Cl is about 20 to 30 mL/min following oral administration. Topiramate half-life is 21 h.

Special Populations

Renal Function Impairment

Cl is reduced 42% in moderately impaired and 54% in severely impaired patients.

Hepatic Function Impairment

Cl may be decreased.

Children

Pediatric patients have a 50% higher Cl and shorter half-life than adults. Consequently, plasma concentrations for the same mg/kg dose may be lower in children than adults.

Indications and Usage

Initial monotherapy for partial onset or primary generalized tonic-clonic seizures; adjunctive therapy for partial onset seizures, primary generalized tonic-clonic seizures, seizures associated with Lennox-Gastaut syndrome, prophylaxis of migraine headache.

Unlabeled Uses

Adjunctive therapy for bipolar disorder, alcohol and cocaine dependence, binge eating disorder, bulimia nervosa, cluster headaches, infantile spasms, weight loss or obesity, and smoking.

Contraindications

Standard considerations.

Dosage and Administration

Epilepsy, adjunctive therapy
Adults 17 yr of age and older

PO 200 to 400 mg daily in 2 divided doses in adults with partial seizures and 400 mg daily in 2 divided doses in adults with primary generalized tonic–clonic seizures. Initiate therapy at 25 to 50 mg daily and titrate to an effective dose in increments of 25 to 50 mg weekly. Doses over 400 mg do not improve response. Daily doses above 1,600 mg have not been studied.

Children 2 to 16 yr of age

PO 5 to 9 mg/kg/day in 2 divided doses. Initiate therapy at 25 mg or less (based on range of 1 to 3 mg/kg/day) nightly for first wk and titrate to an effective dose at 1- to 2-wk intervals by increments of 1 to 3 mg/kg/day in 2 divided doses.

Epilepsy, monotherapy
Adults and Children 10 yr of age and older

PO 400 mg daily in 2 divided doses. Initiate therapy at 50 mg daily and titrate to an effective dose in increments of 25 to 50 mg weekly.

Migraine
Adults

PO 50 mg in the morning and evening. Clinical outcome guides dose and titration rate; however, the recommended titration rate is:

• Week 1: 25 mg in the evening.
• Week 2: 25 mg in the morning and evening.
• Week 3: 25 mg in the morning and 50 mg in the evening.
• Week 4: 50 mg in the morning and evening.

Renal Function Impairment (CrCl less than 70 mL/min)

Dosage adjustment of 50% of the usual adult dose is recommended.

General Advice

• Sprinkle capsules may be swallowed whole or administered by carefully opening the capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. The mixture should be swallowed immediately and not chewed. Do not store for future use.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Store capsules at temperatures below 77°F. Keep tightly capped and protect from moisture.

Drug Interactions

Alcohol, CNS depressants

CNS depression and adverse reactions may be increased.

Amitriptyline

Plasma concentrations may be increased by topiramate.

Carbamazepine

Effects of topiramate may be decreased.

Carbonic anhydrase inhibitors (eg, acetazolamide)

Increased risk of renal stone formation.

Contraceptives, oral

Efficacy of oral contraceptives may be decreased; there is a possibility of increased breakthrough bleeding.

Digoxin, lithium

Plasma concentrations may be decreased by topiramate.

Hydrochlorothiazide, lamotrigine

Topiramate plasma concentrations may be increased.

Metformin

Plasma concentrations may be increased by topiramate, while topiramate oral Cl may be reduced.

Phenytoin

Effects of phenytoin may be increased, while those of topiramate may decrease.

Pioglitazone

Plasma concentrations of the active metabolites of pioglitazone may be decreased.

Risperidone

Exposure to risperidone may be decreased.

Valproic acid

Effects of valproic acid and topiramate may be decreased. The risk of hyperammonemia may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (2%); bradycardia (1%).

CNS

Paresthesia (51%); dizziness (32%); fatigue (30%); somnolence (29%); psychomotor slowing (21%); nervousness (19%); ataxia (16%); confusion, difficulty with concentration, difficulty with memory (14%); depression, speech disorders (13%); behavior problems, mood problems, nystagmus (11%); language problems (10%); aggressive reaction, insomnia, tremor (9%); abnormal gait, hypoaesthesia (8%); cognitive problems (7%); anxiety (6%); hyperkinesia (5%); abnormal coordination, involuntary muscle contraction (4%); agitation, apathy, decreased libido, emotional liability, hypertonia (3%); aggravated depression, depersonalization, hyporeflexia, stupor, vertigo (2%); aggravated migraine, convulsions, headache, sensory disturbance, syncope (1% or more).

Dermatologic

Alopecia (5%); pruritus, rash (4%); acne, skin disorder (3%); dermatitis, erythematous rash, hypertrichosis (2%); eczema, increased sweating, seborrhea, skin discoloration (1%); bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), pemphigus (postmarketing).

EENT

Taste perversion (15%); abnormal vision (13%); diplopia (10%); pharyngitis (6%); blurred vision (4%); conjunctivitis, decreased hearing, eye abnormality, otitis media, tinnitus (2%); abnormal accommodation, abnormal lacrimation, eye pain, myopia (1% or more).

GI

Anorexia (24%); nausea (14%); diarrhea (11%); abdominal pain, dyspepsia (7%); increased saliva (6%); constipation, dry mouth (5%); gastritis, gastroenteritis, vomiting (3%); gastroesophageal reflux, taste loss (2%); dysphagia, fecal incontinence, flatulence, GI disorder, gingivitis, glossitis, gum hyperplasia, tooth disorder (1% or more); pancreatitis (postmarketing).

Genitourinary

Breast pain, urinary incontinence, UTI (4%); cystitis, menstrual disorder, premature ejaculation, renal calculus, vaginal hemorrhage (3%); amenorrhea, dysuria, hematuria, leukorrhea, menorrhagia, micturition frequency, prostatic disorder (2%); abnormal urine, genital moniliasis, intermenstrual bleeding, nocturia (1% or more); renal tubular acidosis (postmarketing).

Hematologic

Purpura (8%); epistaxis (4%); anemia, leukopenia (2%); hematoma, increased PT, thrombocytopenia (1%).

Hepatic

Gamma-GT increased (3%); hepatic failure (including fatalities), hepatitis (postmarketing).

Metabolic

Weight decrease (21%); thirst (2%); hypoglycemia, increased appetite, weight increase (1%).

Musculoskeletal

Arthralgia (7%); leg cramps, myalgia (2%).

Respiratory

Upper respiratory tract infection (18%); sinusitis (10%); bronchitis, rhinitis (7%); pneumonia (5%); coughing (4%); dyspnea (3%); asthma, respiratory disorder (1% or more).

Miscellaneous

Injury (14%); fever, viral infection (9%); infection (7%); asthenia (6%); back pain (5%); chest pain, flu-like symptoms, leg pain (4%); allergy (3%); allergic reaction, edema, hot flushes, neoplasm (2%); body odor, moniliasis, neurosis, pallor, pain, rigors, skeletal pain (1% or more).

Precautions

Monitor Measurement of baseline and periodic serum bicarbonate is recommended.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Treatment of epilepsy

Safety and efficacy not established in children younger than 2 yr of age for adjunctive treatment and younger than 10 yr of age for monotherapy.

Treatment of migraine

Safety and efficacy not established.

Elderly

Consider age-related changes in renal function.

Renal Function

Reduce dose 50% if CrCl less than 70 mL/min.

Hepatic Function

Administer with caution.

Acute myopia

Acute myopia secondary to angle-closure glaucoma has been reported.

Hemodialysis

Supplemental dose may be necessary before prolonged dialysis.

Kidney stones

Risk of developing kidney stones may be increased.

Metabolic acidosis

Hyperchloremic, non-anion gap, metabolic acidosis has been associated with topiramate treatment.

Oligohidrosis and hyperthermia

Have been reported, mostly in children.

Sudden death

Sudden unexplained death in epilepsy has been reported at an incidence of 0.0035 per patient year.

Withdrawal

Gradually withdraw therapy to minimize potential of increased seizure frequency.

Overdosage

Symptoms

Abdominal pain, abnormal coordination, agitation, blurred vision, convulsions, death, depression, diplopia, dizziness, drowsiness, hypotension, lethargy, mentation impaired, severe metabolic acidosis, speech disturbance, stupor.

Patient Information

• Advise patient, family, or caregiver to read the patient information leaflet before starting therapy and with each refill.
• Instruct patient, family, or caregiver to continue other medications for seizures unless advised to do otherwise by health care provider.
• Advise patient, family, or caregiver that medication will be started at a low dose and then gradually increased as tolerated until max benefit has been obtained.
• Instruct patient, family, or caregiver to take (give) exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
• Advise patient using topiramate for migraine prophylaxis that medication must be taken daily as prescribed to prevent migraine headaches. Inform patient that topiramate does not work when taken as needed to try to treat a migraine headache.
• Advise patient to swallow tablet whole. Chewing the tablet may leave a bitter taste.
• Advise patient, family, or caregiver that sprinkle capsules may be swallowed whole or opened and the entire contents sprinkled onto a small amount (eg, teaspoon) of soft food (eg, applesauce) and then consumed immediately without chewing. Advise patient, family, or caregiver to give fluid (eg, water) to help wash the sprinkle/food mixture down. Caution patient, family, or caregiver not to prepare ahead of time and store for future use.
• Advise patient, family, or caregiver that each dose may be taken without regard to meals but to take with food if stomach upset occurs.
• Instruct patient, family, or caregiver that if a dose is missed to skip that dose and not double the next dose.
• Advise patient, family, or caregiver to maintain adequate fluid intake to reduce chance of developing kidney stones.
• Instruct patient, family, or caregiver to discontinue therapy and immediately contact health care provider of any of the following: sudden change in vision; blurred vision, eye pain, or pain around the eye; decreased sweating and elevated body temperature; unexplained rapid breathing or shortness of breath; pounding in the chest or abnormal heart rhythm; stupor.
• Advise patient, family, or caregiver that if medication needs to be discontinued, it will be slowly withdrawn over a period of 2 wk or more unless safety concerns (eg, rash) require a more rapid withdrawal.
• Advise patient to avoid alcoholic beverages and other depressants while taking this medication.
• Caution patient that drug may cause dizziness, drowsiness, confusion, or difficulty concentrating and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
• Advise patient that topiramate may cause weight loss and to consider additional food intake if weight loss occurs.
• Advise women using oral contraceptives that topiramate may reduce their effectiveness and to consider using an alternate method of contraception.
• Advise patient that medication may cause photosensitivity (sensitivity to sunlight) and to avoid unnecessary exposure to UV light (sunlight, tanning booths), use sunscreen, and wear protective clothing when exposed to UV light until tolerance is determined.
• Instruct patient, family, or caregiver to contact health care provider if seizures get worse or if new types of seizures occur.
• Advise patient, family, or caregiver to contact health care provider if bothersome adverse reactions occur.
• Advise patient to carry identification (eg, card, bracelet) indicating medication usage and epilepsy.

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