Summary Of Exposure |
A) USES: Levetiracetam is as adjunct for the treatment of myoclonic seizures, partial onset seizures, and generalized tonic-clonic seizures.
B) PHARMACOLOGY: The exact mechanism of action is unknown but does not involve inhibitory and excitatory neurotransmission. Stereoselective binding of levetiracetam was confined to synaptic plasma membranes in the central nervous system with no binding occurring in peripheral tissue. Levetiracetam inhibits burst firing without affecting normal neuronal excitability, which suggests that it may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.
C) EPIDEMIOLOGY: Overdoses are rare.
D) WITH THERAPEUTIC USE
1) MOST COMMON (5% AND GREATER): Somnolence, asthenia, infection, dizziness, fatigue, aggression, nasal congestion, decreased appetite, and irritability. OTHER EFFECTS: Increased diastolic blood pressure, rash, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, hyponatremia, abdominal pain, constipation, diarrhea, gastroenteritis, nausea and vomiting, pancreatitis, severe urinary incontinence, diplopia, amblyopia, elevated liver enzymes, hepatitis, hepatic failure, hypersensitivity reactions, neck pain, coordination difficulties (eg, ataxia, abnormal gait, incoordination), nervousness, headache, memory impairment, dyskinesia, choreoathetosis, ataxia, vertigo, headache, behavioral symptoms (eg, agitation, hostility, anxiety, apathy, emotional lability, depersonalization, and depression), cough, pharyngitis, rhinitis, sinusitis, decreased red blood cell count, hemoglobin, hematocrit, white blood cell count, and neutrophil count, increased eosinophil count, and agranulocytosis.
E) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Overdose data are limited. Vomiting, drowsiness, apathy, profound hypotonia, ataxia, agitation, and aggression have been reported.
2) SEVERE TOXICITY: Coma, bradycardia, hypotension, and respiratory depression have been reported.
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Diplopia and amblyopia have been reported in 2% of levetiracetam-treated patients (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) INCREASED DIASTOLIC ARTERIAL PRESSURE 1) WITH THERAPEUTIC USE a) In a randomized, placebo-controlled study of patients 1 month to less than 4 years of age, 17% of levetiracetam-treated patients developed increased diastolic blood pressure compared with 2% of placebo-treated patients. This did not occur in studies of older pediatric patients or in adults (Prod Info SPRITAM(R) oral suspension tablets, 2016).
B) BRADYCARDIA 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 43-year-old woman presented with mild CNS depression (Glasgow Coma Scale 14; verbal 4), bradycardia (HR 45 beats/min), hypotension (BP 86/57 mmHg), and oliguria 8 hours after ingesting 60 to 80 g of levetiracetam, 20 tablets of acetaminophen/codeine combination (500 mg/30 mg), and an unknown quantity of ethanol. Laboratory results revealed serum levetiracetam concentration of 462.5 mg/L and non-toxic levels of acetaminophen at 8 hours postingestion. Her baseline full blood count and biochemistry were normal. Despite treatment with atropine and IV fluid, she remained bradycardic and hypotensive. Following further supportive care, her blood pressure and heart rate gradually improved and she was discharged home 48 hours after levetiracetam overdose with normal vital signs. An analysis of the pharmacokinetic parameters revealed a concentration-time profile that was similar to that of therapeutic doses with a half-life of 10.4 hours, an absorption coefficient of 1.32/hour, and a Vd of 75 L. It is concluded that levetiracetam-induced cardiotoxicity may be due to the effect of levetiracetam acting at M2 and M3 muscarinic receptors at very high concentrations (Page et al, 2016).
C) HYPOTENSIVE EPISODE 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 43-year-old woman presented with mild CNS depression (Glasgow Coma Scale 14; verbal 4), bradycardia (HR 45 beats/min), hypotension (BP 86/57 mmHg), and oliguria 8 hours after ingesting 60 to 80 g of levetiracetam, 20 tablets of acetaminophen/codeine combination (500 mg/30 mg), and an unknown quantity of ethanol. Laboratory results revealed serum levetiracetam concentration of 462.5 mg/L and non-toxic levels of acetaminophen at 8 hours postingestion. Her baseline full blood count and biochemistry were normal. Despite treatment with atropine and IV fluid, she remained bradycardic and hypotensive. Following further supportive care, her blood pressure and heart rate gradually improved and she was discharged home 48 hours after levetiracetam overdose with normal vital signs. An analysis of the pharmacokinetic parameters revealed a concentration-time profile that was similar to that of therapeutic doses with a half-life of 10.4 hours, an absorption coefficient of 1.32/hour, and a Vd of 75 L. It is concluded that levetiracetam-induced cardiotoxicity may be due to the effect of levetiracetam acting at M2 and M3 muscarinic receptors at very high concentrations (Page et al, 2016).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) RESPIRATORY FAILURE 1) WITH POISONING/EXPOSURE a) CASE REPORT: An adult presented with coma and respiratory failure (Glasgow Coma Score 8, shallow respirations at 12/minute, O2 saturation 70% on 100% O2) 6 hours after ingesting 30 g of levetiracetam (Barrueto et al, 2002).
B) ACUTE RESPIRATORY INFECTIONS 1) WITH THERAPEUTIC USE a) Respiratory symptoms have been reported following levetiracetam therapy in clinical trials. Reported effects have included coughing (2%), pharyngitis (6%), rhinitis (4%), and sinusitis (2%) (Prod Info SPRITAM(R) oral suspension tablets, 2016).
C) NASAL CONGESTION 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, nasal congestion developed in 9% of 165 pediatric patients (oral route, immediate release; aged 4 to 16 years) receiving levetiracetam compared with 2% of 131 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
D) COUGH 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, cough developed in 9% of 165 pediatric patients (oral route, immediate release; aged 4 to 16 years) receiving levetiracetam compared with 5% of 131 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
E) PHARYNGITIS 1) WITH THERAPEUTIC USE a) In clinical trials, 7% of levetiracetam-treated patients (n=60) compared with 0% of placebo patients (n=60) developed pharyngitis (Prod Info SPRITAM(R) oral suspension tablets, 2016).
F) NASOPHARYNGITIS 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, nasopharyngitis developed in 15% of 165 pediatric patients (oral route, immediate release; aged 4 to 16 years) receiving levetiracetam compared with 12% of 131 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
G) PNEUMONIA 1) WITH THERAPEUTIC USE a) CASE REPORT: A 65-year-old woman, who presented with epileptic crisis, developed pancytopenia following treatment with levetiracetam, and subsequently developed pneumonia and multiple liver abscesses. On day 18 of levetiracetam treatment, the patient developed dyspnea and fever. Levetiracetam and paroxetine were discontinued. The patient's platelet and WBC counts started to increase 6 days following levetiracetam discontinuation. On day 30 of hospitalization the patient no longer had a fever and her chest x-ray revealed a obvious reduction in pneumonia. However, on day 60 of hospitalization, multiple liver abscesses, common bile duct lithiasis and bacterial strains were found. Subsequent to antibiotics therapy (vancomycin, metronidazole, ciprofloxacin and meropenem), the patient's condition gradually improved and she was discharged in stable condition on day 94 with normalized laboratory results and resolution of liver abscesses. Subsequent follow-up visits (2, 4, and 9 months) were normal. The relationship between pancytopenia and use of levetiracetam was considered possible based on the Naranjo score of +3 (Gallerani et al, 2009).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) DROWSY 1) WITH THERAPEUTIC USE a) In controlled trials, somnolence developed in 15% of adult patients with epilepsy experiencing partial onset seizures receiving levetiracetam compared with 8% of placebo-treated patients. With no titration, 45% of patients receiving 4000 mg/day of levetiracetam reported somnolence (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) Sedation typically occurs within the first 4 weeks of treatment with the immediate release formulation (Prod Info SPRITAM(R) oral suspension tablets, 2016).
c) Incidence of somnolence and fatigue was similar in pediatric patients with partial onset seizures compared with adult patients during clinical trials (Prod Info SPRITAM(R) oral suspension tablets, 2016).
2) WITH POISONING/EXPOSURE a) CASE REPORT: A 43-year-old woman presented with mild CNS depression (Glasgow Coma Scale 14; verbal 4), bradycardia (HR 45 beats/min), hypotension (BP 86/57 mmHg), and oliguria 8 hours after ingesting 60 to 80 g of levetiracetam, 20 tablets of acetaminophen/codeine combination (500 mg/30 mg), and an unknown quantity of ethanol. Laboratory results revealed serum levetiracetam concentration of 462.5 mg/L and non-toxic levels of acetaminophen at 8 hours postingestion. Her baseline full blood count and biochemistry were normal. Despite treatment with atropine and IV fluid, she remained bradycardic and hypotensive. Following further supportive care, her blood pressure and heart rate gradually improved and she was discharged home 48 hours after levetiracetam overdose with normal vital signs. An analysis of the pharmacokinetic parameters revealed a concentration-time profile that was similar to that of therapeutic doses with a half-life of 10.4 hours, an absorption coefficient of 1.32/hour, and a Vd of 75 L. It is concluded that levetiracetam-induced cardiotoxicity may be due to the effect of levetiracetam acting at M2 and M3 muscarinic receptors at very high concentrations (Page et al, 2016).
b) CASE SERIES: In an 11-year retrospective observational case series of 82 pediatric (median age: 2 years; range, 1 to 60 months) levetiracetam ingestions (oral solutions: 62 cases; immediate-release tablets: 20 cases), 33 cases with the exact dose ingested (median dose: 45 mg/kg; range: 10.5 to 1429 mg/kg) were identified, with 29 cases involving the ingestion of oral solution of levetiracetam. Although there was no dose-response relationship, the odds of a levetiracetam nonuser (acute ingestions; median dose, 26.9 mg/kg; N=15) with an unintentional exposure, developing drowsiness or ataxia was 6 times that of patient who was a previous user (acute-on-chronic or chronic ingestions) of levetiracetam (median dose, 70.1 mg/kg; N=20). Of the 82 cases, drowsiness, ataxia, and both drowsiness with ataxia developed in 2, 11, and 1 patients, respectively. One patient, a 2-month-old, was admitted to the hospital after inadvertently receiving 10 times the usual dose of levetiracetam. Another patient, a 3-year-old, developed lethargy and was admitted to the hospital after ingesting an unknown amount of levetiracetam. Other patients were released from the ED after supportive care. No effects, minor effects, and moderate effects were observed in 66 patients (80.5%), 15 patients (18.3%), and one patient (1.2%), respectively. No major effects or deaths were observed in any patients (Lewis et al, 2014).
c) CASE REPORT: A 10-month-old girl with multidrug refractory epilepsy and Ohtahara syndrome, presented with drowsiness, apathy, and profound hypotonia after inadvertently receiving 300 mg/kg/day of levetiracetam (10 times the recommended dose) for 35 days. Concomitant medications included vigabatrin, topiramate, calcium folinate, and vitamin B6. All laboratory results were normal. Following supportive care, her condition improved and she was discharged with her correct dose of levetiracetam after 7 days (Ozkale et al, 2014).
B) COMA 1) WITH POISONING/EXPOSURE a) CASE REPORT: An adult presented comatose (Glasgow Coma Score 8) 6 hours after ingesting 30 g of levetiracetam (Barrueto et al, 2002).
C) DRUG-INDUCED ENCEPHALOPATHY 1) WITH THERAPEUTIC USE a) CASE REPORT: A 28-year-old man suffering from idiopathic epilepsy developed increased seizure frequency and encephalopathy described as impaired neuropsychological function (i.e. impaired word fluency, psychomotor speed and working memory) after levetiracetam (3000 mg) was added to his regimen consisting of valproic acid. Following discontinuation of levetiracetam, his symptoms improved (Bauer, 2008).
D) FEELING NERVOUS 1) WITH THERAPEUTIC USE a) Approximately 4% of levetiracetam treated patients have reported nervousness (Prod Info SPRITAM(R) oral suspension tablets, 2016).
E) FEELING IRRITABLE 1) WITH THERAPEUTIC USE a) Non-psychotic behavioral disorders, including irritability, have been reported with levetiracetam use (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) In pooled placebo-controlled studies, irritability developed in 7% of 165 pediatric patients (oral route, immediate release; aged 4 to 16 years) receiving levetiracetam compared with 1% of 131 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
F) AMNESIA 1) WITH THERAPEUTIC USE a) Dose-related adverse effects reported in clinical trials with levetiracetam have included memory impairment, depression, dysarthria, and cognitive or mood changes (eg, agitation, aggressive behavior, euphoria). These effects generally resolve spontaneously or after dosage reduction (Haria & Balfour, 1997; Sharief et al, 1996; Kasteleijn-Nolstlt Trenite et al, 1996; Chevalier et al, 1995; Patsalos & Sander, 1994).
G) DELIRIUM 1) WITH THERAPEUTIC USE a) CASE REPORT: A 77-year-old man presented with a 1-day history of progressively worsening lethargy, fever (102 degrees F), and an irregular heart rhythm. All laboratory results, including infectious workup, were normal. Brain imaging revealed a subacute subdural hematoma in the left frontal lobe without associated mass effect. The next day, he received levetiracetam 500 mg IV every 12 hours for the prevention of posttraumatic seizures. Within 12 hours of receiving levetiracetam, he developed a fluctuating level of consciousness, disorientation, alternating agitation and lethargy, inability to follow commands, and garbled speech that continued for more than 10 days. Despite treatment with IV dexmedetomidine, haloperidol, lorazepam, and quetiapine, his condition did not improve. His condition was markedly improved within 24 hours of discontinuing levetiracetam and he was discharged the following day (Hwang et al, 2014).
H) DYSKINESIA 1) WITH THERAPEUTIC USE a) Dyskinesia has been reported during postmarketing surveillance of levetiracetam (Prod Info SPRITAM(R) oral suspension tablets, 2016).
I) CHOREOATHETOSIS 1) WITH THERAPEUTIC USE a) Choreoathetosis has been reported during postmarketing surveillance of levetiracetam (Prod Info SPRITAM(R) oral suspension tablets, 2016).
J) ATAXIA 1) WITH THERAPEUTIC USE a) In controlled clinical studies, coordination difficulties, including ataxia, abnormal gait, and incoordination, occurred in 3.4% of adult patients with partial onset seizures as compared with 1.6% of placebo-treated patients (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) Coordination difficulties most frequently occurred during the first 4 weeks of treatment (Prod Info SPRITAM(R) oral suspension tablets, 2016).
2) WITH POISONING/EXPOSURE a) CASE SERIES: In an 11-year retrospective observational case series of 82 pediatric (median age: 2 years; range, 1 to 60 months) levetiracetam ingestions (oral solutions: 62 cases; immediate-release tablets: 20 cases), 33 cases with the exact dose ingested (median dose: 45 mg/kg; range: 10.5 to 1429 mg/kg) were identified, with 29 cases involving the ingestion of oral solution of levetiracetam. Although there was no dose-response relationship, the odds of a levetiracetam nonuser (acute ingestions; median dose, 26.9 mg/kg; N=15) with an unintentional exposure, developing drowsiness or ataxia was 6 times that of patient who was a previous user (acute-on-chronic or chronic ingestions) of levetiracetam (median dose, 70.1 mg/kg; N=20). Of the 82 cases, drowsiness, ataxia, and both drowsiness with ataxia developed in 2, 11, and 1 patients, respectively. One patient, a 2-month-old, was admitted to the hospital after inadvertently receiving 10 times the usual dose of levetiracetam. Another patient, a 3-year-old, developed lethargy and was admitted to the hospital after ingesting an unknown amount of levetiracetam. Other patients were released from the ED after supportive care. No effects, minor effects, and moderate effects were observed in 66 patients (80.5%), 15 patients (18.3%), and one patient (1.2%), respectively. No major effects or deaths were observed in any patients (Lewis et al, 2014).
K) ABNORMAL GAIT 1) WITH THERAPEUTIC USE a) In controlled clinical studies, coordination difficulties, including ataxia, abnormal gait, and incoordination, occurred in 3.4% of adult patients with partial onset seizures as compared with 1.6% of placebo-treated patients (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) Coordination difficulties most frequently occurred during the first 4 weeks of treatment (Prod Info SPRITAM(R) oral suspension tablets, 2016).
L) DIZZINESS 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, dizziness developed in 9% of 769 patients receiving levetiracetam compared with 4% of 439 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
M) VERTIGO 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, vertigo developed in 3% of 769 patients receiving levetiracetam compared with 1% of 439 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
N) ASTHENIA 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, asthenia developed in 15% of 769 patients receiving levetiracetam compared with 9% of 439 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) Asthenia generally occurs during the first 4 weeks of treatment with immediate release formulation (Prod Info SPRITAM(R) oral suspension tablets, 2016).
O) HEADACHE 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, asthenia developed in 14% of 769 patients receiving levetiracetam compared with 13% of 439 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) In pooled placebo-controlled studies, asthenia developed in 19% of 165 pediatric patients (oral route, immediate release; aged 4 to 16 years) receiving levetiracetam compared with 15% of 131 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
P) IMPAIRED COGNITION 1) WITH THERAPEUTIC USE a) Studies report that cognitive changes have occurred (Haria & Balfour, 1997a; Sharief et al, 1996a; Wilson & Brodie, 1996; Kasteleijn-Nolst Trenite et al, 1996; Chevalier et al, 1995; Patsalos & Sander, 1994a)
b) This effect appears to be dose-related and generally resolves spontaneously or after dosage reduction (Haria & Balfour, 1997a; Sharief et al, 1996a; Wilson & Brodie, 1996; Kasteleijn-Nolst Trenite et al, 1996; Chevalier et al, 1995; Patsalos & Sander, 1994a)
Q) FATIGUE 1) WITH THERAPEUTIC USE a) In pooled placebo-controlled studies, fatigue developed in 11% of 165 pediatric patients (oral route, immediate release; aged 4 to 16 years) receiving levetiracetam compared with 5% of 131 patients receiving placebo plus existing antiepileptic drug therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) Incidence of somnolence and fatigue was similar in pediatric patients with partial onset seizures compared with adult patients during clinical trials (Prod Info SPRITAM(R) oral suspension tablets, 2016).
c) There were no dose reductions or treatment discontinuation due to fatigue in clinical studies (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) GASTRITIS 1) WITH THERAPEUTIC USE a) Levetiracetam-treated patients reported anorexia, abdominal pain, constipation, diarrhea, gastroenteritis, nausea and vomiting (Prod Info SPRITAM(R) oral suspension tablets, 2016). Nausea is a dose-related effect (Kasteleijn-Nolstlt Trenite et al, 1996).
2) WITH POISONING/EXPOSURE a) CASE REPORT: An adult who ingested 30 g of levetiracetam developed vomiting 4 hours later (Barrueto et al, 2002).
B) PANCREATITIS 1) WITH THERAPEUTIC USE a) Pancreatitis has been reported (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Elevations of liver enzymes have been reported rarely with piracetam administration (Wilsher et al, 1987). A cause-effect relationship has not been established.
B) INFLAMMATORY DISEASE OF LIVER 1) WITH THERAPEUTIC USE a) Hepatitis has been reported (Prod Info SPRITAM(R) oral suspension tablets, 2016).
C) HEPATIC FAILURE 1) WITH THERAPEUTIC USE a) Hepatic failure has been reported (Prod Info SPRITAM(R) oral suspension tablets, 2016). However, a cause-effect relationship has not been established.
b) CASE REPORT: A 21-year-old man developed fulminant liver failure one month after starting levetiracetam. He presented with jaundice, pale stools, and dark urine. Autoimmune, vital and metabolic liver screens were negative. Although levetiracetam was discontinued, the patient still went on to require a liver transplant. Levetiracetam was then restarted only to be accompanied by rapid deterioration of the transplanted liver function. Following the discontinuation of levetiracetam, the transplanted liver recovered 4 days later (Tan et al, 2008).
c) CASE REPORT: A 22-year-old woman with a history of developmental delay developed fulminant liver failure and ultimately died. She had been on both carbamazepine and levetiracetam for treatment of seizure disorder. Excessive drug concentrations were not present (Skopp et al, 2006).
D) ABSCESS OF LIVER 1) WITH THERAPEUTIC USE a) CASE REPORT: A 65-year-old woman, who presented with epileptic crisis, developed pancytopenia following treatment with levetiracetam, and subsequently developed pneumonia and multiple liver abscesses. On day 18 of levetiracetam treatment, the patient developed dyspnea and fever. Levetiracetam and paroxetine were discontinued. The patient's platelet and WBC counts started to increase 6 days following levetiracetam discontinuation. On day 30 of hospitalization the patient no longer had a fever and her chest x-ray revealed a obvious reduction in pneumonia. However, on day 60 of hospitalization, multiple liver abscesses, common bile duct lithiasis and bacterial strains were found. Subsequent to antibiotics therapy (vancomycin, metronidazole, ciprofloxacin and meropenem), the patient's condition gradually improved and she was discharged in stable condition on day 94 with normalized laboratory results and resolution of liver abscesses. Subsequent follow-up visits (2, 4, and 9 months) were normal. The relationship between pancytopenia and use of levetiracetam was considered possible based on the Naranjo score of +3 (Gallerani et al, 2009).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) URINARY INCONTINENCE 1) WITH THERAPEUTIC USE a) Severe urinary incontinence was associated with the use of levetiracetam in a 46-year-old man. This resolved upon the discontinuation of the drug (Morrell et al, 2003).
B) OLIGURIA 1) WITH POISONING/EXPOSURE a) CASE REPORT: A 43-year-old woman presented with mild CNS depression (Glasgow Coma Scale 14; verbal 4), bradycardia (HR 45 beats/min), hypotension (BP 86/57 mmHg), and oliguria 8 hours after ingesting 60 to 80 g of levetiracetam, 20 tablets of acetaminophen/codeine combination (500 mg/30 mg), and an unknown quantity of ethanol. Laboratory results revealed serum levetiracetam concentration of 462.5 mg/L and non-toxic levels of acetaminophen at 8 hours postingestion. Her baseline full blood count and biochemistry were normal. Despite treatment with atropine and IV fluid, she remained bradycardic and hypotensive. Following further supportive care, her blood pressure and heart rate gradually improved and she was discharged home 48 hours after levetiracetam overdose with normal vital signs. An analysis of the pharmacokinetic parameters revealed a concentration-time profile that was similar to that of therapeutic doses with a half-life of 10.4 hours, an absorption coefficient of 1.32/hour, and a Vd of 75 L. It is concluded that levetiracetam-induced cardiotoxicity may be due to the effect of levetiracetam acting at M2 and M3 muscarinic receptors at very high concentrations (Page et al, 2016).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) ANEMIA 1) WITH THERAPEUTIC USE a) Decreases in total mean red blood cell counts (0.03 x 10(6)/square millimeter), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%) were seen in patients treated with levetiracetam in clinical trials (Prod Info SPRITAM(R) oral suspension tablets, 2016).
B) LEUKOPENIA 1) WITH THERAPEUTIC USE a) A significant decrease in white blood cell count (less than 2.8 x 10(9)/L) was seen in 3.2% of levetiracetam patients versus 1.8% of placebo patients (Prod Info SPRITAM(R) oral suspension tablets, 2016).
C) NEUTROPENIA 1) WITH THERAPEUTIC USE a) A decreased neutrophil count (less than 1 x 10(9)/L) occurred in 2.4% of levetiracetam treated patients versus 1.4% of placebo patients (Prod Info SPRITAM(R) oral suspension tablets, 2016).
D) PANCYTOPENIA 1) WITH THERAPEUTIC USE a) Pancytopenia, including bone marrow suppression in some cases, has been reported (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) CASE REPORT: A 65-year-old woman who presented with epileptic crisis, developed pancytopenia following treatment with levetiracetam, and subsequently developed pneumonia and multiple liver abscesses On day 18 of levetiracetam treatment, the patient developed dyspnea and fever. Levetiracetam and paroxetine were discontinued. On day 30 of hospitalization the patient no longer had a fever and her chest x-ray revealed an obvious reduction in pneumonia. However, on day 60 of hospitalization, multiple liver abscesses, common bile duct lithiasis and bacterial strains were found. Subsequent to antibiotics therapy (vancomycin, metronidazole, ciprofloxacin and meropenem), the patient's condition gradually improved and she was discharged in stable condition on day 94 with normalized laboratory results and resolution of liver abscesses. Subsequent follow-up visits (2, 4, and 9 months) were normal. The relationship between pancytopenia and use of levetiracetam was considered possible based on the Naranjo score of +3(Gallerani et al, 2009).
c) CASE REPORT: A 76-year-old woman developed pancytopenia 2 days after treatment initiation with levetiracetam for a seizure. Initial treatment of levetiracetam 1 g/day IV was added to existing clonazepam therapy. Two days following levetiracetam initiation, the patient developed pancytopenia and levetiracetam was discontinued. Upon rechallenge with oral levetiracetam 0.5 g/day for 2 days, the patient developed pancytopenia again and required another 2 units of packed RBC transfusion. Levetiracetam therapy was permanently discontinued, and clobazam was initiated. The CBC remained in normal range after the patient was discharged from the hospital. Based on the Naranjo probability scale, levetiracetam-induced pancytopenia was deemed probable (Elouni et al, 2009).
E) PLATELET COUNT BELOW REFERENCE RANGE 1) WITH THERAPEUTIC USE a) Thrombocytopenia has been reported (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) CASE REPORT: Levetiracetam was identified as the probable cause of thrombocytopenia (platelet count less than 150,000/m(2)) in a 35-year-old HIV-positive man with AIDS and generalized epilepsy. The only change to his medication regimen was upward titration of levetiracetam to the current dose 2 months prior to admission (Sahaya et al, 2010).
F) PLATELET DYSFUNCTION DUE TO DRUGS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 75-year-old man with a history of left facio-brachial focal motor seizures experienced an alteration in platelet function following treatment with levetiracetam. Inherited thrombopathy was also ruled out. Similar pattern persisted for another 4 days, so the suspected drug, levetiracetam was replaced with lamotrigine. His aggregation profile normalized 3 weeks later. While subarachnoid hemorrhage resolved spontaneously, the patient presented 5 months later with another cerebral bleeding, suggesting cerebral amyloid angiopathy. Levetiracetam, with structurally related molecular structure as piracetam, appears to inhibit thromboxane-dependent platelet activation and aggregation (Hacquard et al, 2009).
G) EOSINOPHILIA 1) WITH THERAPEUTIC USE a) Increases in eosinophil count (10% or more increase or 0.7 X 10(9)/L or greater) occurred in 8.6% of levetiracetam treated patients versus 6.1% of placebo patients (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) CASE REPORT: A 24-year-old man with quadriplegia due to C4-C5 fracture was admitted to the ICU for altered mental status and facial twitching 4 days after experiencing a tonic-clonic seizure. He had a history of seizures 7 years prior, but was not taking antiepileptic medications. Chronic medications before admission included lubiprostone, omeprazole, venlafaxine, doxazosin, enoxaparin, methenamine, metformin, clonidine, baclofen, and diazepam. Ertapenem, gentamicin, vancomycin, and fluconazole were started empirically 2 days before admission. After admission, a loading dose of 2000 mg levetiracetam was given upon admission, and continued at 1000 mg twice daily. Vancomycin, ceftriaxone, and acyclovir were started for empiric coverage of meningitis. Temperature, and WBC, neutrophil, and eosinophil counts were normal; on day 2 intermittent fevers were observed and persistent fever began on day 3. Multiple antimicrobial agents were initiated, and while some organisms were identified by microbiologic culture, none were suspected to be the cause of the fever. Fever continued intermittently through day 11, when all antimicrobials except micafungin were discontinued. Eosinophil elevations had begun on day 8, and on day 14 eosinophil counts were at 9% of WBC count. At this point, levetiracetam was discontinued and changed to phenytoin. The patient's temperature normalized the next day, remaining normal until discharge. The eosinophilia normalized over the next 3 weeks. A Naranjo score of 7 was determined, indicating a probable adverse drug reaction to levetiracetam (Flannery et al, 2015).
H) AGRANULOCYTOSIS 1) WITH THERAPEUTIC USE a) Agranulocytosis has been reported in postmarketing experience (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) ERUPTION 1) WITH THERAPEUTIC USE a) Rash has been reported following levetiracetam therapy (Prod Info SPRITAM(R) oral suspension tablets, 2016).
B) ERYTHEMA MULTIFORME 1) WITH THERAPEUTIC USE a) Erythema multiforme has been reported (Prod Info SPRITAM(R) oral suspension tablets, 2016).
C) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE 1) WITH THERAPEUTIC USE a) Serious dermatological reactions, including toxic epidermal necrolysis, have been reported in patients following administration of levetiracetam. Median time to onset was 14 to 17 days, but symptoms have been reported up to 4 months after treatment initiation (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) CASE REPORTS: Two patients (a 20-year-old woman and a 29-year-old woman) presented with toxic epidermal necrolysis (TEN) with greater than 50% skin detachment. Since both patients were using multiple drugs, including levetiracetam, the specific Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN), Naranjo method, and French Pharmacovigilance (FPV) method were used to assess drug causality. Overall, levetiracetam and loxapine in patient 1 and levetiracetam and metronidazole in patient 2 were determined to be the potential culprit drugs (Duong et al, 2013).
D) STEVENS-JOHNSON SYNDROME 1) WITH THERAPEUTIC USE a) Serious dermatological reactions, including Stevens-Johnson syndrome, have been reported in adult and pediatric patients following administration of levetiracetam. Median time to onset was 14 to 17 days, but symptoms have been reported up to 4 months after treatment initiation (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) NECK PAIN 1) WITH THERAPEUTIC USE a) In clinical trials, 8% of levetiracetam-treated patients (n=60) compared with 2% of placebo patients (n=60) developed neck pain (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) DRUG HYPERSENSITIVITY SYNDROME 1) WITH THERAPEUTIC USE a) Drug reaction with eosinophilia and systemic symptoms has been reported in postmarketing experience (Prod Info SPRITAM(R) oral suspension tablets, 2016).
b) CASE REPORT: A 33-year-old woman with a prior history of hypersensitivity reaction to antiepileptic drug (AED) therapy for bilateral periventricular heterotopia-related seizures developed angioedema after a single dose of levetiracetam 500 mg monotherapy. Intermittent rash developed when phenytoin monotherapy resumed, which also resolved after phenytoin was withdrawn for an evaluation for surgical treatment. The patient was on no other medications when levetiracetam was administered one week later Resolution of swelling occurred within 24 hours and rash within 3 days with IV norepinephrine, steroid, and antihistamine treatment(Alkhotani & McLachlan, 2012).
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Reproductive |
3.20.1) SUMMARY
A) Levetiracetam is classified as US FDA pregnancy category C. There are no adequate and well-controlled studies on the use of levetiracetam in pregnancy. However, similar to other antiepileptic drugs, levetiracetam concentrations may be affected due to physiological changes that occur during pregnancy. Decreased levetiracetam concentrations have been reported during pregnancy, which were more pronounced during the third trimester. Discontinuation of levetiracetam during pregnancy may increase seizure frequency and result in maternal or fetal harm. Close monitoring during pregnancy and the postpartum period is recommended, especially in patients who received a dose change. Levetiracetam is excreted into breast milk. Therefore, it is recommended that due to the potential for adverse reactions in nursing infants, either nursing or the drug should be discontinued. The importance of the drug to the mother should be taken into consideration.
3.20.2) TERATOGENICITY
A) CONGENITAL ANOMALY 1) In an analysis of data collected by the Australian Pregnancy Register from 1999 through 2010 (n=1317), the incidence of fetal malformations that occurred with prenatal exposure to antiepileptic (AED) drug therapy during the first trimester was similar among women who used new AEDs (lamotrigine, levetiracetam, or topiramate), women with epilepsy untreated with AEDs, and women who used traditional AEDs (carbamazepine, clonazepam, or phenytoin), with the exception of valproic acid. The incidence of fetal malformations was 12/231 (5.2%), 0/22 (0%), and 1/31 (3.2%) among patients treated with lamotrigine, levetiracetam, and topiramate monotherapy, respectively, compared with 19/301 (6.3%), 0/24 (0%), 1/35 (2.9%) and 35/215 (16.3%) among patients treated with carbamazepine, clonazepam, phenytoin, or valproate monotherapy, respectively. Fetal malformations were reported in 6/139 (5.2%) of patients who were not treated with AEDs for at least the first trimester (Vajda et al, 2012).
2) Data reported from the UK and Ireland Epilepsy and Pregnancy Register from October 2000 through August 2011 described 671 pregnancies exposed to levetiracetam during the first trimester, in which 93.3% resulted in live birth, and of these, 21 had a major congenital malformation (3.3%). Major malformations occurred in 2 babies (0.7%) exposed prenatally to levetiracetam as monotherapy (n=304) and in 19 cases (6.47%) where levetiracetam was part of a polytherapy anti-epileptic drug regimen (n=367); no dose response was evident for polytherapy exposures. For monotherapy exposures, the mean levetiracetam dose for those with major congenital malformations was 3000 mg/day compared with 1148 mg/day for minor malformations and 1680 mg/day for normal pregnancy outcomes. The most common major congenital malformation was spina bifida (n=5) with all cases occurring in the polytherapy exposure group. The rate of major congenital malformations for polytherapy exposures varied by the antiepileptic drug given concomitantly with levetiracetam. The lamotrigine and levetiracetam combination resulted in a rate of 1.8% compared with 6.9% for valproate and levetiracetam (significant 41% increased risk) and 9.4% for carbamazepine and levetiracetam combinations (significant 91% increased risk). Women taking topiramate and levetiracetam concomitantly had 20 live births, and of these, none had major congenital malformations (Mawhinney et al, 2013).
3) Normal pregnancies and deliveries with levetiracetam use have been reported in a three patient case series. All three patients had initiated levetiracetam prior to conception and maintained treatment throughout gestation at doses ranging from 750 to 3000 milligrams daily. Cognitive alterations, developmental delays, medical problems, or birth defects were not detected over 6 months postnatally. Levetiracetam serum concentrations and breastfeeding history were not obtained (Long & L, 2003).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) Levetiracetam is classified as pregnancy category C (Prod Info SPRITAM(R) oral suspension tablets, 2016).
2) It is recommended that levetiracetam be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus (Prod Info SPRITAM(R) oral suspension tablets, 2016).
B) PREGNANCY REGISTRY 1) Encourage patients to call 1-888-233-2334 to enroll in the North American Antiepileptic Drug Pregnancy Registry or visit http://www.aedpregnancyregistry.org to obtain information on the registry (Prod Info SPRITAM(R) oral suspension tablets, 2016).
C) PREGNANCY KINETICS 1) There are no adequate and well-controlled studies on the use of levetiracetam in pregnancy. However, similar to other antiepileptic drugs, levetiracetam concentrations may be affected due to physiological changes that occur during pregnancy. Decreased levetiracetam concentrations have been reported during pregnancy, which were more pronounced during the third trimester. Discontinuation of levetiracetam during pregnancy may increase seizure frequency and result in maternal or fetal harm. Close monitoring during pregnancy and the postpartum period is recommended, especially in patients who received a dose change (Prod Info SPRITAM(R) oral suspension tablets, 2016).
2) CASE REPORT: Consecutive pregnancies (21) in 20 women with epilepsy receiving levetiracetam were studied retrospectively. Serum concentrations of levetiracetam declined significantly in the third trimester of pregnancy and increased rapidly after delivery. However, pronounced inter-individual variability was present (Westin et al, 2008).
D) PLACENTAL TRANSFER 1) In a prospective study of 14 women (age range, 21 to 37 years) treated with levetiracetam 1000 mg to 3000 mg/day (15 pregnancies), the mean umbilical cord/maternal plasma concentration ratio at birth was 1.09 (range, 0.64 to 2; n=13). Neonatal plasma levetiracetam concentrations were followed after birth and continued to decline to an average of 20% (range, 8 to 54%) of cord plasma levels at 36 hours postpartum; the mean elimination half-life of 18 hours (range, 6 to 28). With the exception of 1 stillbirth (at gestational week 36), all women had full-term pregnancies, delivering healthy children (Tomson et al, 2007).
2) In a study of 8 consecutive pregnant, epileptic women, extensive transplacental transport of levetiracetam was evident following levetiracetam doses of 2000 mg to 3500 mg/day in 4 of the 8 women. The mean umbilical cord serum/maternal serum ratio of levetiracetam was 1.14 (range, 0.97 to 1.45). Among evaluable data, 7 exposed infants (maternal dose, 1500 mg to 3500 mg/day) had a mean birth weight of 3650 g (range, 2970 to 4220 g), were without malformations, and did not develop adverse effects. Infant serum concentrations continued to decline and, 3 to 5 days after delivery, 6 of the infants had very low levetiracetam serum concentrations (less than 10 to 15 micromoles) (Johannessen et al, 2005).
3) CASE REPORT: A mother who had been taking levetiracetam during pregnancy delivered healthy twins. Several samples, including amniotic fluid, umbilical cord blood, and venous blood, were obtained 36 hours or less after birth. The estimated serum half-life at birth was 16 to 18 hours (Allegaert et al, 2006).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) Levetiracetam is excreted into breast milk. Therefore, it is recommended that due to the potential for adverse reactions in nursing infants, either nursing or the drug should be discontinued. The importance of the drug to the mother should be taken into consideration (Prod Info SPRITAM(R) oral suspension tablets, 2016).
2) In a prospective study of 14 women treated with levetiracetam 1000 mg to 3000 mg/day (15 pregnancies, 11 breastfed infants), the mean milk/maternal plasma concentration ratio prior to nursing was 1.05 (range, 0.78 to 1.55; n=11), measured from 4 to 23 days after delivery. When measured after nursing, the infant/maternal plasma concentration ratio was 0.13 (range, 0.07 to 0.22, n=10). The relative infant dose of levetiracetam was estimated as approximately 2.4 mg/kg/day, which was 7.9% of the weight adjusted maternal dose. No adverse effects in the nursing infants were reported (Tomson et al, 2007).
3) A study of 8 consecutive, breastfeeding, epileptic women demonstrated extensive transfer of levetiracetam into breast milk. The women received levetiracetam twice daily, with a daily dose ranging from 1500 to 3500 mg/day. The mean milk/maternal serum concentration ratio of levetiracetam at 3 to 5 days postpartum was 1 (range, 0.76 to 1.33; n=7). At 2 weeks to 10 months postpartum, the range was 0.85 to 1.38 in 5 mother-infant pairs. Notably, at 3 to 5 days after delivery, 6 of the infants had very low levetiracetam serum concentrations (less than 10 to 15 micromoles). All infants appeared to be healthy throughout the study (Johannessen et al, 2005).
3.20.5) FERTILITY
A) LACK OF EFFECT 1) No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to approximately 6 times the maximum recommended human dose on a mg/m2 or exposure basis (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) LACK OF EFFECT 1) In animal studies, no carcinogenic effects were observed when animals received levetiracetam for 104 weeks at doses up to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m(2) basis. In addition, levetiracetam did not increase the risk of developing tumors in animals administered about 5 times the MRHD on a mg/m(2) basis (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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Genotoxicity |
A) In studies, levetiracetam was not mutagenic (in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay) or clastogenic (in an in vitro analysis of metaphase chromosomes from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay). In addition, the hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay (Prod Info SPRITAM(R) oral suspension tablets, 2016).
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