Topiramate

• Migraine, prevention

Oral: Initial: 25 mg once daily; increase the dose in 25 to 50 mg increments at intervals ≥1 week based on response and tolerability, up to 100 mg/day in 1 to 2 divided doses based on chosen formulation. Some patients may require up to 200 mg/day for optimal response; however, adverse effects may increase.

• Seizures

Monotherapy: Oral: Initial: 50 mg/day; increase dose in 50 mg increments at weekly intervals based on response and tolerability up to 200 mg/day in 1 to 2 divided doses based on chosen formulation; after that, may further increase in 100 mg increments at weekly intervals up to 400 mg/day in 1 to 2 divided doses based on chosen formulation.

Adjunctive therapy: Oral: Initial: 25 to 50 mg/day; increase in 25 to 50 mg increments at weekly intervals based on response and tolerability up to 400 mg/day in 1 to 2 divided doses based on chosen formulation.

• Alcohol use disorder, moderate to severe (off-label use)

Oral: Immediate release: Initial: 25 mg once daily; increase the daily dose gradually (eg, in 25 to 50 mg increments weekly) to a maximum of 300 mg/day. Doses >50 mg/day should be administered in 2 divided doses. Some experts consider alternative therapy if goals are not met within 6 months of treatment.

• Binge eating disorder (off-label use)

Oral: Initial: 25 mg once daily; increase the dose gradually in progressively larger increments of 25 to 100 mg at intervals ≥1 week based on response and tolerability up to 400 mg/day in 1 to 2 divided doses based on chosen formulation.

• Cluster headache (off-label use)

Oral: Initial: 25 to 50 mg once daily; increase the dose gradually in 25 to 50 mg increments at intervals ≥1 week based on response and tolerability, up to a recommended dose of 100 mg/day in 1 to 2 divided doses based on chosen formulation; a further increase up to 200 mg/day may be necessary in some patients for optimal response.

• Headache, short-lasting unilateral neuralgiform attacks (off-label use)

Oral: Initial: 15 to 25 mg once daily; may increase the dose based on response and tolerability in 25 mg increments every 2 weeks up to 100 mg/day in 1 to 2 divided doses based on chosen formulation, and after that in 50 mg increments every few weeks up to 400 mg/day in 1 to 2 divided doses based on selected formulation.

• Tremor, essential (off-label use)

Oral: Initial: 25 mg once or twice daily; increase the dose gradually in increments of 25 to 50 mg at intervals ≥1 week based on response and tolerability up to 400 mg/day in 1 to 2 divided doses based on chosen formulation.

• Weight gain, antipsychotic-induced (off-label use)

Oral: Initial: 50 mg/day; increase in 25 to 50 mg increments at weekly intervals based on response and tolerability up to a recommended dose of 200 mg/day in 1 to 2 divided doses based on chosen formulation.

• Acute Myopia and Secondary Angle Closure Glaucoma Syndrome

A syndrome of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving Topiramate. Symptoms include acute onset of decreased visual acuity and ocular pain. Ophthalmologic findings can consist of some or all the following: myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. 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 Topiramate 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 and adults. The primary treatment to reverse symptoms is discontinuing Topiramate as rapidly as possible, according to the treating physician's judgment. Other measures, in conjunction with the discontinuation of Topiramate, may be helpful. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious sequelae, including permanent vision loss.

• Visual Field Defects

Visual field defects (independent of elevated intraocular pressure) have been reported in clinical trials and in post-marketing experience in patients receiving topiramate. In clinical trials, most of these events were reversible after topiramate discontinuation. If visual problems occur at any time during topiramate treatment, consideration should be given to discontinuing the drug.

• Oligohidrosis And Hyperthermia

Oligohidrosis (decreased sweating), infrequently resulting in hospitalization, has been reported in association with Topiramate use. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the issuesissues were reported after exposure to elevated environmental temperatures. Many of the reports have been on pediatric patients. Patients (especially pediatric patients) treated with Topiramate should be monitored closely for evidence of decreased sweating and increased body temperature, especially in hot weather. Caution should be used when Topiramate is given with other drugs predisposing patients to heat-related disorders; these drugs include, but are not limited to, other carbonic anhydrase inhibitors and drugs with anticholinergic activity.

• Decrease In Bone Mineral Density

Results of a one-year active-controlled study in pediatric patients (N=63) demonstrated adverse effects of Topiramate monotherapy on bone mineral acquisition via statistically significant decreases in bone mineral density (BMD) measured in the lumbar spine and in total body less head. Twenty-one percent of Topiramate-treated patients experienced clinically important reductions in BMD (Z score change from baseline of –0.5 or greater) compared to 0 patients in the control group. Although decreases in BMD occurred across all pediatric age subgroups, patients 6 to 9 years of age were most affected. The sample size and study duration were too small to determine if fracture risk is increased. Decreased BMD in the lumbar spine was correlated with reduced serum bicarbonate, which commonly occurs with Topiramate treatment and reflects metabolic acidosis, a known cause of increased bone resorption. Although small decreases in some markers of bone metabolism (e.g., serum alkaline phosphatase, calcium, phosphorus, and 1,25dihydroxyvitamin D) occurred in Topiramate treated patients, more significant decreases in serum parathyroid hormone and 25-hydroxyvitamin D, hormones involved in bone metabolism, were observed, along with an increased excretion of urinary calcium.

• Negative Effects on Growth (Height and Weight)

Results of a one-year active-controlled study of pediatric patients (N=63) demonstrated adverseadverse effects of Topiramate monotherapy on growth (i.e., height and weight). Although continued growth was observed in both treatment groups, the Topiramate group showed statistically significant reductions in mean annual change from baseline in body weight compared to the control group. A similar trend of attenuation in height velocity and height change from baseline was also observed in the Topiramate group compared to the control group. Negative effects on weight and height were seen across all Topiramate age subgroups. Growth (height and weight) of children receiving prolonged Topiramate therapy should be carefully monitored.

• Serious Skin Reactions

Common

 Numbness, burning, or tingling in the hands or feet, slowed reactions, nervousness, headache, drowsiness, weakness, uncontrollable shaking of a part of the body, uncontrollable eye movements, weight loss, constipation, nausea, stomach pain, change in ability to taste food, dry mouth, nosebleed, back, muscle, leg, or bone pain, missed menstrual periods, excessive menstrual bleeding.

Rare

Rash, skin blisters, or skin peeling, blurred vision, loss of vision, double vision,eye pain, eye redness, worsening of seizures, feeling cold, chills, or low body temperature, difficulty concentrating, speech problems, especially difficulty thinking of specific words, confusion, memory problems, coma (loss of consciousness for a period of time), loss of coordination, pounding or irregular heartbeat, chest pain, shortness of breath or trouble breathing, fast, excessive tiredness, diarrhoea, vomiting, loss of appetite, intense back or side pain, bloody, cloudy, or foul-smelling urine, the constant need to urinate, difficulty urinating or pain when urinating, fever or other signs of infection, unusual bleeding or bruising.

Antiepileptic Drugs

Potential interactions between topiramate and standard AEDs were assessed in controlled clinical pharmacokinetic studies in patients with epilepsy. Concomitant administration of phenytoin or carbamazepine with topiramate decreased plasma concentrations of topiramate by 48% and 40%, respectively when compared to Topiramate given alone. Concomitant administration of valproic acid and Topiramate has been associated with hyperammonemia with and without encephalopathy. Concomitant administration of Topiramate with valproic acid has also been associated with hypothermia (with and without hyperammonemia) in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported.

CNS Depressants

Concomitant administration of Topiramate 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 reactions, Topiramate should be used with extreme caution if used in combination with alcohol and other CNS depressants.

Metformin

Topiramate treatment can frequently cause metabolic acidosis, a condition for which metformin is contraindicated.

Lithium

In patients, lithium levels were unaffected during treatment with topiramate at doses of 200 mg/day; however, there was an observed increase in systemic exposure of lithium (27% for Cmax and 26% for AUC) following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when co-administered with high-dose Topiramate.

Other Carbonic Anhydrase Inhibitors

Concomitant use of topiramate, a carbonic anhydrase inhibitor, with any other carbonic anhydrase inhibitor (e.g., zonisamide, acetazolamide, or dichlorphenamide) may increase the severity of metabolic acidosis and may also increase the risk of kidney stone formation. Therefore, if Topiramate is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis.

The common side effects of Topiramate include the following

Common side effects

Blurred vision, dizziness, unusual tiredness and weakness, stomach pain, Loss of appetite, Back pain, Constipation, Drowsiness, Memory problems, Changes in menstrual cycle, Confusion, Weight loss, Chills and fever, Nausea.

Rare side effects

• Pregnancy

Pregnancy Category D

Topiramate can cause fetal harm when administered to a pregnant woman. Data from pregnancy registries indicate that infants exposed to topiramate in utero have an increased risk for cleft lip and/or cleft palate (oral clefts). When multiple pregnant animals received topiramate at clinically relevant doses, structural malformations, including craniofacial defects, and reduced fetal weights occurred in offspring. Topiramate should be used during pregnancy only if the potential benefit outweighs the potential risk. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

• Nursing Mothers

Limited data on 5 breastfeeding infants exposed to topiramate showed infant plasma topiramate levels equal to 10-20% of the maternal plasma level. The effects of this exposure on infants are unknown. Caution should be exercised when administered to a nursing woman.

• Pediatric Use

Safety and effectiveness in patients below the age of 2 years have not been established for the adjunctive therapy treatment of partial onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome.

• Geriatric Use

In clinical trials, 3% of patients were over 60. No age-related differences in effectiveness or adverse effects were evident. However, clinical studies of topiramate did not include enough subjects aged 65 and over to determine whether they respond differently than younger subjects. Dosage adjustment may be necessary for elderly with impaired renal function (creatinine clearance rate.

Symptoms: Convulsions, drowsiness, blurred vision, diplopia, dizziness, abdominal pain, speech disturbances, impaired mentation, lethargy, abnormal coordination, stupor, hypotension, agitation, depression, and severe metabolic acidosis.

Management: Supportive treatment. Ensure the patient is well hydrated. Consider performing hemodialysis.

• Pharmacodynamic

Topiramate prevents the occurrence of seizures and prevents migraine symptoms by reducing neural pathway excitability.

• Pharmacokinetics

Absorption

Topiramate is rapidly and well absorbed. Its Bioavailability is approximately 80% (conventional form). The time taken to reach peak plasma concentration is 0.5 hours (oral solution); 2-3 hours (tab/conventional)

Distribution

Topiramate is having a volume of distribution of about 0.6-0.8 L/kg. It is 15-41% bound to Plasma protein.

Metabolism and Excretion

Topiramate is metabolized in the liver via hydroxylation, hydrolysis, and glucuronidation to form metabolites. It is excreted Via urine approximately 70% as an unchanged drug.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020844s041lbl.pdf
• https://go.drugbank.com/drugs/DB00273
• https://www.drugs.com/mtm/topiramate.html
• https://www.uptodate.com/contents/topiramate-drug-information?search=topiramate&source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://medlineplus.gov/druginfo/meds/a697012.html
• https://www.rxlist.com/topiramate/generic-drug.htm