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warnings and cautions
5 WARNINGS AND PRECAUTIONS CNS Depression: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of alcohol or other CNS depressants. ( 5.2 , 5.4 , 7.2 ) Suicidal Behavior and Ideation: Antiepileptic drugs increase the risk of suicidal thoughts and behavior. ( 5.5 ) Glaucoma: Can increase intraocular pressure; use in patients with open-angle glaucoma only if receiving appropriate therapy. ( 4 , 5.6 ) 5.1 Risk s from Concomitant Use with Opioids Concomitant use of benzodiazepines, including LIBERVANT, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe LIBERVANT concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise caregivers about the risks of respiratory depression and sedation when LIBERVANT is used with opioids [see Drug Interactions ( 7.1 )] . 5.2 Abuse, Misuse, and Addiction LIBERVANT is approved for use in pediatric patients 2 to 5 years of age. The unapproved use of LIBERVANT exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence ( 9.2 )] . 5.3 Dependence and Withdrawal Reactions After Use of LIBERVANT Mor e Fr e quently Than Recommended For patients using LIBERVANT more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue LIBERVANT (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines may lead to clinically significant physical dependence. Although LIBERVANT is indicated only for intermittent use [see Indications and Usage ( 1 ) and Dosage and Administration ( 2 )] , if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of LIBERVANT, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence ( 9.3 )] . Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence ( 9.3 )] . 5.4 Central Nervous System (CNS) Depression Because LIBERVANT produces CNS depression, patients receiving this drug, who are otherwise capable and qualified to do so should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle, until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits. Although LIBERVANT is indicated for use solely on an intermittent basis, the potential for a synergistic CNS-depressant effect when used simultaneously with alcohol or other CNS depressants must be considered by the prescriber, and appropriate recommendations made to the patient and/or caregiver. 5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LIBERVANT, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 100 0 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Drug Events in Drug Patients / Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing LIBERVANT, or any other AED, must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.6 Glaucoma Benzodiazepines, including LIBERVANT, can increase intraocular pressure in patients with glaucoma. LIBERVANT may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. LIBERVANT is contraindicated in patients with narrow-angle glaucoma. 5.7 Neonatal Sedation and Withdrawal Syndrome LIBERVANT is not approved for use in adolescents and adults. Unapproved use of LIBERVANT in adolescents and adults late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations ( 8.1 )]. Monitor neonates exposed to LIBERVANT during pregnancy or labor for signs of sedation and monitor neonates exposed to LIBERVANT during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative LIBERVANT is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including LIBERVANT. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (LIBERVANT contains 3.96 to 11.87 mg of benzyl alcohol per buccal film) [see Use in Specific Populations ( 8.4 )] .