### STATUS EPILEPTICUS

The safety and effectiveness of ATIVAN for status epilepticus have not been established in pediatric patients. A randomized, double-blind, superiority-design clinical trial of ATIVAN versus intravenous diazepam in 273 pediatric patients ages 3 months to 17 years failed to establish the efficacy of ATIVAN for the treatment of status epilepticus. In that trial, assisted ventilation was required in 18% of patients treated with ATIVAN versus 16% of patients treated with diazepam. Patients treated with ATIVAN were also more likely to be reported as sedated (67% for ATIVAN vs. 50% for diazepam), and the time for return to baseline mental status was, on average, 2 hours longer for ATIVAN than for diazepam. 

Open-label studies described in the medical literature included 273 pediatric patients; the age range was from a few hours old to 18 years of age. Paradoxical excitation was observed in 10% to 30% of the pediatric patients under 8 years of age and was characterized by tremors, agitation, euphoria, logorrhea, and brief episodes of visual hallucinations. Paradoxical excitation in pediatric patients also has been reported with other benzodiazepines when used for status epilepticus, as an anesthesia, or for pre-chemotherapy treatment.

Pediatric patients (as well as adults) with atypical petit mal status epilepticus have developed brief tonic-clonic seizures shortly after ATIVAN was given. This “paradoxical” effect was also reported for diazepam and clonazepam. Nevertheless, the development of seizures after treatment with benzodiazepines is probably rare, based on the incidence in the uncontrolled treatment series reported (i.e., seizures were not observed for 112 pediatric patients and 18 adults or during approximately 400 doses).

ATIVAN Injection contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages greater than 99 mg/kg/day in neonates and low-birth-weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

### PREANESTHETIC

There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age.

### GENERAL

Seizure activity and myoclonus have been reported to occur following administration of ATIVAN Injection, especially in very low birth weight neonates.

Pediatric patients may exhibit a sensitivity to benzyl alcohol, polyethylene glycol and propylene glycol, components of ATIVAN Injection (see CONTRAINDICATIONS). The “gasping syndrome”, characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine, has been associated with the administration of intravenous solutions containing the preservative benzyl alcohol in neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Central nervous system toxicity, including seizures and intraventricular hemorrhage, as well as unresponsiveness, tachypnea, tachycardia, and diaphoresis have been associated with propylene glycol toxicity. Although normal therapeutic doses of ATIVAN Injection contain very small amounts of these compounds, premature and low-birth-weight infants as well as pediatric patients receiving high doses may be more susceptible to their effects.

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as ATIVAN that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately 3 years of age in humans.

In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates and young children who require procedures with the potential risks suggested by the nonclinical data. (see WARNINGS, Pediatric Neurotoxicity; PRECAUTIONS, Pregnancy; ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY).