ADVERSE REACTIONS
The prescriber should be aware that the adverse event incidence figures in the following tables, obtained when KEPPRA was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences 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 figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied.
Partial Onset Seizures
In well-controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse events associated with the use of KEPPRA in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness. In the well-controlled pediatric clinical study in children 4 to 16 years of age with partial onset seizures, the adverse events most frequently reported with the use of KEPPRA in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, accidental injury, hostility, nervousness, and asthenia.
Table 8 lists treatment-emergent adverse events that occurred in at least 1% of adult epilepsy patients treated with KEPPRA participating in placebo-controlled studies and were numerically more common than in patients treated with placebo. Table 9 lists treatment-emergent adverse events that occurred in at least 2% of pediatric epilepsy patients (ages 4-16 years) treated with KEPPRA participating in the placebo-controlled study and were numerically more common than in pediatric patients treated with placebo. In these studies, either KEPPRA or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity.
Table 8: Incidence (%) Of Treatment-Emergent Adverse Events In Placebo-Controlled, Add-On Studies In Adults Experiencing Partial Onset Seizures By Body System (Adverse Events Occurred In At Least 1% Of KEPPRA-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) Body System/
Adverse Event
| KEPPRA
(N=769)
% | Placebo
(N=439)
% |
|---|
| Body as a Whole | | |
| Asthenia | 15 | 9 |
| Headache | 14 | 13 |
| Infection | 13 | 8 |
| Pain | 7 | 6 |
| Digestive System | | |
| Anorexia | 3 | 2 |
| Nervous System | | |
| Somnolence | 15 | 8 |
| Dizziness | 9 | 4 |
| Depression | 4 | 2 |
| Nervousness | 4 | 2 |
| Ataxia | 3 | 1 |
| Vertigo | 3 | 1 |
| Amnesia | 2 | 1 |
| Anxiety | 2 | 1 |
| Hostility | 2 | 1 |
| Paresthesia | 2 | 1 |
| Emotional Lability | 2 | 0 |
| Respiratory System | | |
| Pharyngitis | 6 | 4 |
| Rhinitis | 4 | 3 |
| Cough Increased | 2 | 1 |
| Sinusitis | 2 | 1 |
| Special Senses | | |
| Diplopia | 2 | 1 |
Other events reported by at least 1% of adult KEPPRA-treated patients but as or more frequent in the placebo group were the following: abdominal pain, accidental injury, amblyopia, arthralgia, back pain, bronchitis, chest pain, confusion, constipation, convulsion, diarrhea, drug level increased, dyspepsia, ecchymosis, fever, flu syndrome, fungal infection, gastroenteritis, gingivitis, grand mal convulsion, insomnia, nausea, otitis media, rash, thinking abnormal, tremor, urinary tract infection, vomiting and weight gain.
Table 9: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Pediatric Patients Ages 4-16 Years Experiencing Partial Onset Seizures By Body System (Adverse Events Occurred In At Least 2% Of KEPPRA-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) Body System/
Adverse Event
| KEPPRA
(N=101)
% | Placebo
(N=97)
% |
|---|
| Body as a Whole | | |
| Accidental Injury | 17 | 10 |
| Asthenia | 9 | 3 |
| Pain | 6 | 3 |
| Flu Syndrome | 3 | 2 |
| Face Edema | 2 | 1 |
| Neck Pain | 2 | 1 |
| Viral Infection | 2 | 1 |
| Digestive System | | |
| Vomiting | 15 | 13 |
| Anorexia | 13 | 8 |
| Diarrhea | 8 | 7 |
| Gastroenteritis | 4 | 2 |
| Constipation | 3 | 1 |
| Hemic and Lymphatic System | | |
| Ecchymosis | 4 | 1 |
| Metabolic and Nutritional | | |
| Dehydration | 2 | 1 |
| Nervous System | | |
| Somnolence | 23 | 11 |
| Hostility | 12 | 6 |
| Nervousness | 10 | 2 |
| Personality Disorder | 8 | 7 |
| Dizziness | 7 | 2 |
| Emotional Lability | 6 | 4 |
| Agitation | 6 | 1 |
| Depression | 3 | 1 |
| Vertigo | 3 | 1 |
| Reflexes Increased | 2 | 1 |
| Confusion | 2 | 0 |
| Respiratory System | | |
| Rhinitis | 13 | 8 |
| Cough Increased | 11 | 7 |
| Pharyngitis | 10 | 8 |
| Asthma | 2 | 1 |
| Skin and Appendages | | |
| Pruritus | 2 | 0 |
| Skin Discoloration | 2 | 0 |
| Vesiculobullous Rash | 2 | 0 |
| Special Senses | | |
| Conjunctivitis | 3 | 2 |
| Amblyopia | 2 | 0 |
| Ear Pain | 2 | 0 |
| Urogenital System | | |
| Albuminuria | 4 | 0 |
| Urine Abnormality | 2 | 1 |
Other events occurring in at least 2% of pediatric KEPPRA-treated patients but as or more frequent in the placebo group were the following: abdominal pain, allergic reaction, ataxia, convulsion, epistaxis, fever, headache, hyperkinesia, infection, insomnia, nausea, otitis media, rash, sinusitis, status epilepticus (not otherwise specified), thinking abnormal, tremor, and urinary incontinence.
Myoclonic Seizures
Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.
In the well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult patients with myoclonic seizures, the most frequently reported adverse events associated with the use of KEPPRA in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were somnolence, neck pain, and pharyngitis.
Table 10 lists treatment-emergent adverse events that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with KEPPRA and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity.
Table 10: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Patients 12 Years Of Age And Older With Myoclonic Seizures By Body System (Adverse Events Occurred In At Least 5% Of KEPPRA-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) Body System /
MedDRA preferred term | KEPPRA
(N=60)
% | Placebo
(N=60)
% |
|---|
| Ear and labyrinth disorders | | |
| Vertigo | 5 | 3 |
| Infections and infestations | | |
| Pharyngitis | 7 | 0 |
| Influenza | 5 | 2 |
| Musculoskeletal and connective tissue disorders | | |
| Neck pain | 8 | 2 |
| Nervous system disorders | | |
| Somnolence | 12 | 2 |
| Psychiatric disorders | | |
| Depression | 5 | 2 |
Other events occurring in at least 5% of KEPPRA-treated patients with myoclonic seizures but as or more frequent in the placebo group were the following: fatigue and headache.
Primary Generalized Tonic-Clonic Seizures
Although the pattern of adverse events in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse event pattern for patients with PGTC seizures is expected to be essentially the same as for patients with partial seizures.
In the well-controlled clinical study that included patients 4 years of age and older with primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse event associated with the use of KEPPRA in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis.
Table 11 lists treatment-emergent adverse events that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with KEPPRA and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy. Adverse events were usually mild to moderate in intensity.
Table 11: Incidence (%) Of Treatment-Emergent Adverse Events In A Placebo-Controlled, Add-On Study In Patients 4 Years Of Age And Older With PGTC Seizures By MedDRA System Organ Class (Adverse Events Occurred In At Least 5% Of KEPPRA-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients) MedDRA System Organ Class/
Preferred Term | KEPPRA
(N=79)
% | Placebo
(N=84)
% |
|---|
| Gastrointestinal disorders | | |
| Diarrhea | 8 | 7 |
| General disorders and administration site conditions | | |
| Fatigue | 10 | 8 |
| Infections and infestations | | |
| Nasopharyngitis | 14 | 5 |
| Psychiatric disorders | | |
| Irritability | 6 | 2 |
| Mood swings | 5 | 1 |
Other events occurring in at least 5% of KEPPRA-treated patients with PGTC seizures but as or more frequent in the placebo group were the following: dizziness, headache, influenza, and somnolence.
Time Course Of Onset Of Adverse Events For Partial Onset Seizures
Of the most frequently reported adverse events in adults experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with KEPPRA.
Discontinuation Or Dose Reduction In Well-Controlled Clinical Studies
Partial Onset Seizures
In well-controlled adult clinical studies, 15.0% of patients receiving KEPPRA and 11.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. Table 12 lists the most common (>1%) adverse events that resulted in discontinuation or dose reduction.
Table 12: Adverse Events That Most Commonly Resulted In Discontinuation Or Dose Reduction In Placebo-Controlled Studies In Adult Patients Experiencing Partial Onset Seizures | Number (%) |
|---|
| KEPPRA
(N=769) | Placebo
(N=439) |
|---|
| Asthenia | 10 (1.3%) | 3 (0.7%) |
| Convulsion | 23 (3.0%) | 15 (3.4%) |
| Dizziness | 11 (1.4%) | 0 |
| Rash | 0 | 5 (1.1%) |
| Somnolence | 34 (4.4%) | 7 (1.6%) |
In the well-controlled pediatric clinical study, 16.8% of patients receiving KEPPRA and 20.6% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events most commonly associated (≥3% in patients receiving KEPPRA) with discontinuation or dose reduction in the well-controlled study are presented in Table 13.
Table 13: Adverse Events Most Commonly Associated With Discontinuation Or Dose Reduction In The Placebo-Controlled Study In Pediatric Patients Ages 4-16 Years Experiencing Partial Onset Seizures | Number (%) |
|---|
| KEPPRA
(N=101) | Placebo
(N=97) |
|---|
| Asthenia | 3 (3.0%) | 0 |
| Hostility | 7 (6.9%) | 2 (2.1%) |
| Somnolence | 3 (3.0%) | 3 (3.1%) |
Myoclonic Seizures
In the placebo-controlled study, 8.3% of patients receiving KEPPRA and 1.7% receiving placebo either discontinued or had a dose reduction as a result of an adverse event. The adverse events that led to discontinuation or dose reduction in the well-controlled study are presented in Table 14.
Table 14: Adverse Events That Resulted In Discontinuation Or Dose Reduction In The Placebo-Controlled Study In Patients With Juvenile Myoclonic Epilepsy Body System/
MedDRA preferred term | KEPPRA
(N=60)
n (%) | Placebo
(N=60)
n (%) |
|---|
| Anxiety | 2 (3.3%) | 1 (1.7%) |
| Depressed mood | 1 (1.7%) | 0 |
| Depression | 1 (1.7%) | 0 |
| Diplopia | 1 (1.7%) | 0 |
| Hypersomnia | 1 (1.7%) | 0 |
| Insomnia | 1 (1.7%) | 0 |
| Irritability | 1 (1.7%) | 0 |
| Nervousness | 1 (1.7%) | 0 |
| Somnolence | 1 (1.7%) | 0 |
Primary Generalized Tonic-Clonic Seizures
In the placebo-controlled study, 5.1% of patients receiving KEPPRA and 8.3% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of a treatment-emergent adverse event.
This study was too small to adequately characterize the adverse events leading to discontinuation. It is expected that the adverse events that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see tables 12 - 14).
Comparison Of Gender, Age And Race
The overall adverse experience profile of KEPPRA was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse experience reports by age and race.
Postmarketing Experience
In addition to the adverse experiences listed above, the following have been reported in patients receiving marketed KEPPRA worldwide. The listing is alphabetized: abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia, and weight loss. Alopecia has been reported with KEPPRA use; recovery was observed in majority of cases where KEPPRA was discontinued. These adverse experiences have not been listed above, and data are insufficient to support an estimate of their incidence or to establish causation.
DRUG ABUSE AND DEPENDENCE
The abuse and dependence potential of KEPPRA has not been evaluated in human studies.
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