pms-Topiramate

pms-Topiramate Adverse Reactions

topiramate

Manufacturer:

Pharmascience

Distributor:

T-BOMA
Full Prescribing Info
Adverse Reactions
The majority of the most common adverse events in clinical trials were mild to moderate in severity and dose-related. These dose-related adverse events typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase. Rapid titration rate and higher initial dose were associated with higher incidences of adverse events leading to discontinuation.
Epilepsy: Adverse Drug Reaction Overview for Monotherapy: Adults: The most commonly observed adverse events associated with the use of topiramate at dosages of 100 to 400 mg/day in controlled trials in adults with newly diagnosed epilepsy were: paresthesia, fatigue, headache, somnolence, dizziness, upper respiratory tract infection, anorexia, weight decrease, depression, and nausea (see Tables 9a and 9b).
Approximately 19% of the 886 adult patients who received topiramate as monotherapy in controlled clinical trials for patients with newly diagnosed epilepsy discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy included paresthesia (2.6%), somnolence (2.5%), fatigue (2.3%), nausea (2.0%), and psychomotor slowing (1.6%).
Pediatrics: The most commonly observed adverse events associated with the use of topiramate at dosages of 100 to 400 mg/day in controlled trials in children with newly diagnosed epilepsy were: upper respiratory tract infection, headache, anorexia, difficulty with concentration/attention, weight decrease, somnolence, paresthesia, fever, and fatigue (see Tables 10a and 10b).
Approximately 10% of the 245 pediatric patients who received topiramate as monotherapy in controlled clinical trials for patients with newly diagnosed epilepsy discontinued therapy due to adverse events. Adverse events associated with discontinuing therapy included difficulty with concentration/attention (2.0%). No pediatric patients withdrew due to psychomotor slowing.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. (See Tables 9a, 9b, 10a and 10b.)

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Adverse Drug Reaction Overview for Adjunctive Therapy: Adults: The most commonly observed adverse events associated with the adjunctive use of topiramate at dosages of 200 to 400 mg/day in controlled trials in adults that were seen at greater frequency in patients treated with topiramate and did not appear to be dose-related within this dosage range were: somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, nystagmus, and paresthesia (see Table 11).
The most common dose-related adverse events at dosages of 200 to 1,000 mg/day were: nervousness, difficulty with concentration or attention, confusion, depression, anorexia, language problems, and mood problems (see Table 12).
Pediatrics: Adverse events associated with the use of topiramate at dosages of 5 to 9 mg/kg/day in worldwide pediatric clinical trials that were seen at greater frequency in patients treated with topiramate were: fatigue, somnolence, anorexia, nervousness, difficulty with concentration/attention, difficulty with memory, aggressive reaction, and weight decrease (see Table 13).
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. (See Tables 11 and 12.)

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In six double-blind clinical trials, 10.6% of subjects (n = 113) assigned to a topiramate dosage of 200 to 400 mg/day in addition to their standard AED therapy discontinued due to adverse events, compared to 5.8% of subjects (n = 69) receiving placebo. The percentage of subjects discontinuing due to adverse events appeared to increase at dosages above 400 mg/day. Overall, approximately 17% of all subjects (n = 527) who received topiramate in the double-blind trials discontinued due to adverse events, compared to 4% of the subjects (n = 216) receiving placebo.
Table 13 lists treatment-emergent adverse events that occurred in at least 2% of children treated with 5 to 9 mg/kg/day topiramate in controlled trials that were numerically more common than in patients treated with placebo. (See Table 13.)

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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. In open extensions of the controlled clinical trials, approximately 9% of the 303 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%), language problems (1.3%), and difficulty with concentration/attention (1.3%).
When the safety experience of patients receiving topiramate as adjunctive therapy in both double-blind and open-label trials (1,446 adults and 303 children) was analyzed, a similar pattern of adverse events emerged.
Less Common Clinical Trial Adverse Drug Reactions (< 2%): Adverse events that occurred less frequently but were considered potentially medically relevant included: taste perversion, cognitive problems (not otherwise specified) and psychosis/psychotic symptoms.
In adult and pediatric patients, nephrolithiasis was reported rarely. Isolated cases of thromboembolic events have also been reported; a causal association with the drug has not been established.
In clinical trials with topiramate, the occurrence rate for all potential cases of oligohidrosis (decreased sweating) was 0.25%.
In clinical trials for topiramate in epilepsy, migraine prophylaxis and other investigational indications (obesity, bipolar disorder and diabetic peripheral neuropathy), suicide-related adverse events occurred at a rate of 0.8% (84 reports/10,846 patients) in topiramate vs. 0.2% (5 reports/3,150 patients) in placebo groups. Although the average exposure time for patients on topiramate (approximately 10 months) was longer than for those on placebo (approximately 5 months), these adverse events were reported randomly over the exposure period. Suicide attempts occurred in 0.3% (33 reports/10,846 patients) of the topiramate-treated patients compared to 0% in placebo groups. Of these 33 attempts, one completed suicide was reported in a double-blind bipolar disorder trial and three in the open-label phase of the bipolar disorder trials (see Psychiatric: Suicidal Ideation and Behaviour under Precautions).
Suicide-related adverse events include suicidal ideation, suicide attempt, suicide and any evidence of self-harm.
Migraine Prophylaxis: Adverse Drug Reaction Overview: Table 14 includes those adverse events reported for patients in four multicentre, randomized, double-blind, placebo-controlled, parallel-group migraine prophylaxis clinical trials where the incidence rate in any topiramate treatment group was at least 2% and was greater than that for placebo patients. Most of the adverse events were mild or moderate in severity and most occurred more frequently during the titration period than during the maintenance period.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. (See Table 14.)

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Of the 1,135 patients exposed to topiramate in the placebo-controlled studies, 25% discontinued due to adverse events, compared to 10% of the 445 placebo patients. The most common adverse events associated with discontinuing therapy in the topiramate-treated patients included paresthesia (6.7%), fatigue (4.3%), nausea (4.0%), difficulty with concentration/attention (2.9%), insomnia (2.7%), anorexia (2.1%), and dizziness (2.0%).
In the six-month migraine prophylaxis controlled trials, the proportion of patients who experienced one or more cognitive-related event was 19% for topiramate 50 mg/day, 22% for 100 mg/day, 28% for 200 mg/day and 10% for placebo. These dose-related adverse reactions typically began in the titration phase and often persisted into the maintenance phase, but infrequently began in the maintenance phase.
Table 15 shows adverse events that were dose-dependent. (See Table 15.)

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Other Adverse Events Observed During Migraine Clinical Trials: For the prophylactic treatment of migraine headache, topiramate has been administered to 1,367 patients in all clinical studies (includes double-blind and open-label extension). 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 following additional adverse events that were not described earlier were reported by greater than 1% of the 1,367 topiramate-treated patients in the controlled clinical trials: Body as a Whole: pain, chest pain, allergic reaction.
Central and Peripheral Nervous System Disorders: headache, vertigo, tremor, sensory disturbance, migraine aggravated.
Gastrointestinal System Disorders: constipation, gastroesophageal reflux, tooth disorder.
Musculoskeletal System Disorders: myalgia.
Platelet, Bleeding and Clotting Disorders: epistaxis.
Reproductive Disorders, Female: intermenstrual bleeding.
Resistance Mechanism Disorders: infection, genital moniliasis.
Respiratory System Disorders: pneumonia, asthma.
Skin and Appendages Disorders: rash, alopecia.
Vision Disorders: abnormal accommodation, eye pain.
Post-Market Adverse Drug Reactions: In addition to the adverse events reported during clinical trial testing of topiramate, the following adverse drug reactions have been reported in patients receiving marketed topiramate from worldwide use since approval. Adverse drug reactions from spontaneous reports during the worldwide post-marketing experience with topiramate are included in Table 16 as follows. The adverse drug reactions are ranked by frequency, using the following convention (all calculated per patient-years of estimated exposure): Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/1,000 and < 1/100; Rare ≥ 1/10,000 and < 1/1,000; Very rare < 1/10,000.
The frequencies provided as follows reflect reporting rates for adverse drug reactions from spontaneous reports, and do not represent more precise estimates that might be obtained in clinical or experimental studies. (See Table 16.)

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Oligohidrosis (decreased sweating) has been rarely reported with the use of topiramate. The majority of spontaneous post-marketing reports have been in children. Adverse events that may be related to potential cases of oligohidrosis include dehydration, hyperthermia, and heat intolerance. Adequate hydration prior to activities such as exercise or exposure to warm temperatures is recommended (see Endocrine and Metabolism: Oligohidrosis and Hyperthermia under Precautions).
To date, there have been rare spontaneous, post-marketing reports of metabolic acidosis. In some cases, acidosis resolved after dosage reduction or upon discontinuation of topiramate (see Endocrine and Metabolism: Metabolic Acidosis under Precautions).
Rare reports of encephalopathy with or without hyperammonemia have been received for patients treated with topiramate while also taking valproic acid or other antiepileptic medications (see Endocrine and Metabolism: Hyperammonemia and Encephalopathy; Drug-Drug Interactions: Antiepileptic Drugs (AEDs): Effects of Other AEDs on pms-TOPIRAMATE: Valproic Acid under Interactions).
There have been rare spontaneous post-marketing reports of suicide attempts and suicide-related adverse events, including fatalities, in patients treated with topiramate alone or in combination with other medications (see Psychiatric: Suicidal Ideation and Behaviour under Precautions).
Very rare reports of bullous skin and mucosal reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme and pemphigus) have also been received. The majority of these reports have occurred in patients taking other medications that can be associated with bullous skin and mucosal reactions. There have also been several cases in patients receiving monotherapy (see Serious Skin Reactions under Precautions).
The following adverse experiences have not been listed previously and data are insufficient to support an estimate of their incidence or to establish causation.
Reports of increases in liver function tests in patients taking topiramate with and without other medications have been received. Isolated reports have been received of hepatitis and hepatic failure occurring in patients taking multiple medications while being treated with topiramate. (See Table 17.)

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