LIBERVANT is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 2 to 5 years of age.

{ "type": "p", "children": [], "text": "LIBERVANT is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 2 to 5 years of age." }

Prior to treatment, healthcare professionals should instruct the individual administering LIBERVANT on how to identify seizure clusters and use the product appropriately [see Dosage and Administration (2.3) and Patient Counseling Information (17)].

The recommended dose of LIBERVANT is dependent on the patient’s weight and is provided in Table 1.

<div class="scrollingtable"><table> <caption> <span>Table 1:       Recommended Dosage for Pediatric Patients 2 to 5 Years of Age</span> </caption> <colgroup> <col width="200"/> <col width="200"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule"><span class="Bold">Weight</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Libervant Dose</span></td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule">6 kg to 10 kg</td><td align="center" class="Lrule Rrule Toprule">5 mg</td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule">11 kg to 15 kg</td><td align="center" class="Lrule Rrule Toprule">7.5 mg</td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule">16 kg to 20 kg</td><td align="center" class="Lrule Rrule Toprule">10 mg</td> </tr> <tr> <td align="center" class="Lrule Rrule Toprule">21 kg to 25 kg</td><td align="center" class="Lrule Rrule Toprule">12.5 mg</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule Toprule">26 kg to 30 kg</td><td align="center" class="Lrule Rrule Toprule">15 mg</td> </tr> </tbody> </table></div>

Second Dose (if needed): A second dose, when required, may be administered at least 4 hours after the first dose.

Maximum Dosage and Treatment Frequency: Do not use more than 2 doses of LIBERVANT to treat a single episode.

Do not use LIBERVANT to treat more than one episode every five days or more than five episodes per month.

Caregivers should be counseled to read carefully the “Instructions for Use” for complete directions on how to properly administer LIBERVANT.

LIBERVANT is a rectangular green buccal film that dissolves when applied on the inside of the mouth on top of the surface of the cheek. Do not split LIBERVANT, the entire dose should be applied and allowed to dissolve [see Dosage and Administration (2.1)]. Do not administer LIBERVANT buccal film with liquids.

LIBERVANT dosing may be administered without regard to food [see Clinical Pharmacology (12.3)].

LIBERVANT buccal film: green, rectangular, orally dissolving film strips:

{ "type": "p", "children": [], "text": "LIBERVANT buccal film: green, rectangular, orally dissolving film strips:" }

{ "type": "ul", "children": [ "5 mg film imprinted with D5", "7.5 mg film imprinted with D7•5", "10 mg film imprinted with D10", "12.5 mg film imprinted with D12•5", "15 mg film imprinted with D15" ], "text": "" }

LIBERVANT is contraindicated in patients with:

{ "type": "p", "children": [], "text": "LIBERVANT is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Hypersensitivity to diazepam", "Acute narrow-angle glaucoma [see Warnings and Precautions (5.6)]\n" ], "text": "" }

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)].

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)].

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)].

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.

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.

<div class="scrollingtable"><table> <caption> <span>Table 2:       Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</span> </caption> <colgroup> <col width="96"/> <col width="138"/> <col width="124"/> <col width="152"/> <col width="128"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule"><span class="Bold">Indication</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Placebo Patients with Events per 100</span><span class="Bold">0</span><span class="Bold"> Patients</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Drug Patients with Events per 1000 Patients</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Relative Risk: Incidence of Drug Events in Drug Patients / Incidence in Placebo Patients</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Risk Difference: Additional Drug Patients with Events per 1000 Patients</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Epilepsy</td><td align="center" class="Lrule Rrule Toprule">1.0</td><td align="center" class="Lrule Rrule Toprule">3.4</td><td align="center" class="Lrule Rrule Toprule">3.5</td><td align="center" class="Lrule Rrule Toprule">2.4</td> </tr> <tr> <td class="Lrule Rrule Toprule">Psychiatric</td><td align="center" class="Lrule Rrule Toprule">5.7</td><td align="center" class="Lrule Rrule Toprule">8.5</td><td align="center" class="Lrule Rrule Toprule">1.5</td><td align="center" class="Lrule Rrule Toprule">2.9</td> </tr> <tr> <td class="Lrule Rrule Toprule">Other</td><td align="center" class="Lrule Rrule Toprule">1.0</td><td align="center" class="Lrule Rrule Toprule">1.8</td><td align="center" class="Lrule Rrule Toprule">1.9</td><td align="center" class="Lrule Rrule Toprule">0.9</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule">Total</td><td align="center" class="Lrule Rrule Toprule">2.4</td><td align="center" class="Lrule Rrule Toprule">4.3</td><td align="center" class="Lrule Rrule Toprule">1.8</td><td align="center" class="Lrule Rrule Toprule">1.9</td> </tr> </tbody> </table></div>

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.

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.

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.

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)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of LIBERVANT is supported by clinical trials using diazepam rectal gel; pharmacokinetic studies of LIBERVANT in healthy subjects and epilepsy patients; and an open-label long-term safety and tolerability study of LIBERVANT in epilepsy patients.

Diazepam Rectal Gel

In studies previously conducted with diazepam rectal gel, adverse event data were collected from double-blind, placebo-controlled studies and open-label studies. The majority of adverse events were mild to moderate in severity and transient in nature.

Two patients who received diazepam rectal gel died seven to 15 weeks following treatment; neither of these deaths was deemed related to diazepam rectal gel.

The most frequent adverse reactions (at least 5%) in the two double-blind, placebo-controlled studies were somnolence and headache. Table 3 lists adverse reactions that occurred in greater than 1% of patients enrolled in parallel-group, placebo-controlled trials and were numerically more common in the diazepam rectal gel group than placebo. Adverse reactions were usually mild or moderate in intensity.

Approximately 1.4% of the 573 patients who received diazepam rectal gel in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse reaction most frequently associated with discontinuation (occurring in three patients) was somnolence. Other adverse reactions most commonly associated with discontinuation and occurring in two patients were hypoventilation and rash. Adverse reactions associated with discontinuation occurring in one patient were asthenia, hyperkinesia, incoordination, vasodilatation, and urticaria.

In the two double-blind, placebo-controlled, parallel-group studies [see Clinical Studies (14)], the proportion of patients who discontinued treatment because of adverse events was 2% for the group treated with diazepam rectal gel, versus 2% for the placebo group. In the diazepam rectal gel group, one patient discontinued because of rash and one patient discontinued because of lethargy.

<div class="scrollingtable"><table> <caption> <span>Table 3: Adverse Reactions That Occurred in Greater Than 1% Of Patients in Parallel-Group, Placebo-Controlled Trials with Diazepam Rectal Gel and Were More Common Than in the Placebo Group</span> </caption> <colgroup> <col width="207"/> <col width="207"/> <col width="207"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" valign="bottom"><span class="Bold">Adverse Reaction</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Diazepam Rectal Gel</span><span class="Bold"> <br/>N = 101</span><span class="Bold"> <br/>%</span></td><td align="center" class="Lrule Rrule Toprule"><span class="Bold">Placebo</span><span class="Bold"> <br/>N = 104</span><span class="Bold"> <br/>%</span></td> </tr> <tr> <td class="Lrule Rrule Toprule">Somnolence</td><td align="center" class="Lrule Rrule Toprule">23</td><td align="center" class="Lrule Rrule Toprule">8</td> </tr> <tr> <td class="Lrule Rrule">Headache</td><td align="center" class="Lrule Rrule">5</td><td align="center" class="Lrule Rrule">4</td> </tr> <tr> <td class="Lrule Rrule">Diarrhea</td><td align="center" class="Lrule Rrule">4</td><td align="center" class="Lrule Rrule">&lt;1</td> </tr> <tr> <td class="Lrule Rrule">Ataxia</td><td align="center" class="Lrule Rrule">3</td><td align="center" class="Lrule Rrule">&lt;1</td> </tr> <tr> <td class="Lrule Rrule">Dizziness</td><td align="center" class="Lrule Rrule">3</td><td align="center" class="Lrule Rrule">2</td> </tr> <tr> <td class="Lrule Rrule">Euphoria</td><td align="center" class="Lrule Rrule">3</td><td align="center" class="Lrule Rrule">0</td> </tr> <tr> <td class="Lrule Rrule">Incoordination</td><td align="center" class="Lrule Rrule">3</td><td align="center" class="Lrule Rrule">0</td> </tr> <tr> <td class="Lrule Rrule">Rash</td><td align="center" class="Lrule Rrule">3</td><td align="center" class="Lrule Rrule">0</td> </tr> <tr> <td class="Lrule Rrule">Asthma</td><td align="center" class="Lrule Rrule">2</td><td align="center" class="Lrule Rrule">0</td> </tr> <tr class="Last"> <td class="Lrule Rrule">Vasodilatation</td><td align="center" class="Lrule Rrule">2</td><td align="center" class="Lrule Rrule">0</td> </tr> </tbody> </table></div>

LIBERVANT (Diazepam Buccal Film)

Clinical studies, which included patients with epilepsy 2 to 5 years of age, were conducted to support the safety and tolerability of LIBERVANT for the treatment of acute repetitive seizures. A total of 197 patients received LIBERVANT, of whom 107 received LIBERVANT for at least 6 months, and 48 for at least 1 year. The adverse reactions reported in these studies were similar to those seen in efficacy trials of diazepam rectal gel.

Other Adverse Reactions

Diazepam rectal gel was administered to 573 patients with epilepsy during all clinical trials, only some of which were placebo controlled. All of the events listed below occurred in at least 1% of the 573 individuals exposed to diazepam rectal gel.

Body as a Whole: Asthenia

Cardiovascular: Hypotension, vasodilatation

Nervous: Agitation, confusion, convulsion, dysarthria, emotional lability, speech disorder, thinking abnormal, vertigo

Respiratory: Hiccup

The following infrequent adverse events have been reported previously with diazepam use: depression, slurred speech, syncope, constipation, changes in libido, urinary retention, bradycardia, cardiovascular collapse, nystagmus, urticaria, neutropenia, and jaundice.

Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported with other diazepam products. If these events occur with the use of LIBERVANT, the prescriber should consider discontinuation of use.

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids and follow patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1)].

Coadministration of other CNS depressants (e.g., valproate) or consumption of alcohol may potentiate the CNS-depressant effects of diazepam [see Warnings and Precautions (5.2)].

Potential interactions may occur when diazepam is given concurrently with agents that affect CYP2C19 and CYP3A4 activity.

Inhibitors of CYP2C19 and CYP3A4

Inhibitors of CYP2C19 (e.g., cimetidine, quinidine, and tranylcypromine) and CYP3A4 (e.g., ketoconazole, troleandomycin, and clotrimazole) could decrease the rate of diazepam elimination; therefore, adverse reactions to LIBERVANT may be increased.

Inducers of CYP2C19 and CYP3A4

Inducers of CYP2C19 (e.g., rifampin) and CYP3A4 (e.g., carbamazepine, phenytoin, dexamethasone, and phenobarbital) could increase the rate of diazepam elimination; therefore, efficacy of LIBERVANT may be decreased.

Diazepam is a substrate for CYP2C19 and CYP3A4; therefore, it is possible that LIBERVANT may interfere with the metabolism of drugs which are substrates for CYP2C19, (e.g. omeprazole, propranolol, and imipramine) and CYP3A4 (e.g. cyclosporine, paclitaxel, theophylline, and warfarin) leading to a potential drug-drug interaction [see Clinical Pharmacology (12.3)].

LIBERVANT is indicated for treatment in patients 2 to 5 years of age [see Indications and Usage (1)]. LIBERVANT is not approved for use in adolescents and adults.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as LIBERVANT, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women who are taking LIBERVANT during pregnancy enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.7) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (seeHuman Data).

In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Animal Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to LIBERVANT during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to LIBERVANT during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.7)].

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. 

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

Diazepam has been shown to produce increased incidences of fetal malformations in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately 13 times a human dose of 0.6 mg/kg/day or greater on a mg/m2 basis). Cleft palate and exencephaly are the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis.

In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic neurotransmission to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development corresponding to that taking place during the third trimester of pregnancy in humans.

LIBERVANT is indicated for treatment in patients 2 to 5 years of age [see Indications and Usage (1)]. LIBERVANT is not approved for use in adolescents and adults.

Risk Summary

Diazepam is excreted in human milk.

There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data to assess the effects of diazepam and/or its active metabolite(s) on milk production. 

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LIBERVANT and any potential adverse effects on the breastfed infant from LIBERVANT or from the underlying maternal condition.

Clinical Considerations

Infants exposed to LIBERVANT through breast milk should be monitored for sedation, poor feeding, and poor weight gain.

Safety and effectiveness of LIBERVANT have been established in pediatric patients 2 to 5 years of age. Use of LIBERVANT in this age group is supported by evidence from adequate and well-controlled studies of diazepam rectal gel in adult and pediatric patients, adult bioavailability studies comparing LIBERVANT with diazepam rectal gel, pediatric and adult LIBERVANT pharmacokinetic data, and an open-label safety study of LIBERVANT including patients 2 years to 5 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness of LIBERVANT in pediatric patients below the age of 2 and above the age of 5 have not been established.

LIBERVANT is not approved for use in neonates or infants.

LIBERVANT is indicated for treatment in patients 2 to 5 years of age [see Indications and Usage (1)]. LIBERVANT is not approved for use in adults.

Clinical studies of LIBERVANT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

A study of single dose IV administration of diazepam (0.1 mg/kg) indicates that the elimination half-life of diazepam increases linearly with age, ranging from about 15 hours at 18 years (healthy young adults) to about 100 hours at 95 years (healthy elderly) with a corresponding decrease in clearance of free diazepam.

If used in elderly patients, LIBERVANT should be used with caution because of an increase in half life with a corresponding decrease in the clearance of free diazepam [see Clinical Pharmacology (12.3)]. It is also recommended that the dosage be decreased to reduce the likelihood of ataxia or oversedation.

LIBERVANT should be used with caution in patients with compromised respiratory function related to a concurrent disease process (e.g., asthma, pneumonia) or neurologic damage.

LIBERVANT contains diazepam, a Schedule IV controlled substance.

LIBERVANT is a benzodiazepine and a CNS depressant with a potential for abuse and addiction with unapproved use in adolescents and adults. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Physical Dependence After Use of LIBERVANT More Frequently Than Recommended

LIBERVANT may produce physical dependence if used more frequently than recommended. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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 or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)].

For patients using LIBERVANT more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue LIBERVANT [seeWarnings and Precautions (5.3)].

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to LIBERVANT may develop after use more frequently than recommended. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

It is recommended that patients be treated with LIBERVANT no more frequently than one episode every five days and no more than five episodes per month.

LIBERVANT is not recommended for chronic, daily use as an anticonvulsant. Chronic daily use of diazepam may increase the frequency and/or severity of tonic-clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures.

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

{ "type": "p", "children": [], "text": "Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage." }

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

{ "type": "p", "children": [], "text": "In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information." }

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

{ "type": "p", "children": [], "text": "Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations." }

Diazepam, the active ingredient of LIBERVANT, is a benzodiazepine anticonvulsant with the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; its empirical formula is C16H13ClN2O and its molecular weight is 284.7 g/mol. It is an odorless, white to practically white crystalline powder with a pKa of 3.4 and a partition coefficient of 2.9.   It is practically insoluble in water and soluble in 96% ethanol, chloroform, and alcohol. The melting range for diazepam is 131°C to 135°C.The structural formula is as follows:

{ "type": "p", "children": [], "text": "Diazepam, the active ingredient of LIBERVANT, is a benzodiazepine anticonvulsant with the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; its empirical formula is C16H13ClN2O and its molecular weight is 284.7 g/mol. It is an odorless, white to practically white crystalline powder with a pKa of 3.4 and a partition coefficient of 2.9.   It is practically insoluble in water and soluble in 96% ethanol, chloroform, and alcohol. The melting range for diazepam is 131°C to 135°C.The structural formula is as follows:" }

LIBERVANT is a buccal film that contains the active ingredient diazepam. Each film strip contains 5, 7.5, 10, 12.5, or 15mg of diazepam and the following inactive ingredients: benzyl alcohol, clove oil, EDTA disodium salt, FD&C Green #3, glycerol monooleate, hypromellose, peppermint oil, polyethylene oxide, polyvinylpyrrolidone, sodium phosphate, sucralose, vanillin, xanthan gum, water, and white ink.

{ "type": "p", "children": [], "text": "LIBERVANT is a buccal film that contains the active ingredient diazepam. Each film strip contains 5, 7.5, 10, 12.5, or 15mg of diazepam and the following inactive ingredients: benzyl alcohol, clove oil, EDTA disodium salt, FD&C Green #3, glycerol monooleate, hypromellose, peppermint oil, polyethylene oxide, polyvinylpyrrolidone, sodium phosphate, sucralose, vanillin, xanthan gum, water, and white ink." }

The exact mechanism of action for diazepam is not fully understood, but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.

The effects of diazepam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

The pharmacokinetics of diazepam and desmethyldiazepam following administration of LIBERVANT were investigated in adult healthy subjects and in pediatric and adult patients with epilepsy. The pharmacokinetics of diazepam were linear and dose-proportional in the recommended dose range [see Dosage and Administration (2.2)]. In pediatric patients 2 to 5 years of age, median maximum plasma concentration (Cmax) and median area under the plasma concentration curve for 4 hours after dosing (AUC0-4) of diazepam are approximately 2- to 3-times greater than in adults. The higher Cmax and higher AUC0-4 in pediatric patients 2 to 5 years of age are expected to provide adequate therapeutic exposures under both fed and fasted states.

Absorption

Following single doses of LIBERVANT administered to healthy adults under fasting conditions, diazepam peak concentration (Cmax) was reached in approximately 1 hour. 

In pharmacokinetic studies of patients with epilepsy, pharmacokinetic parameters were similar between seizure state and non-seizure state.

Effect of Food

The pharmacokinetics of LIBERVANT were characterized under fasting, moderate fat, and high fat fed conditions in three clinical studies in adults. Under fed conditions a 33%-47% decrease in Cmax, but no significant change in AUC, was observed relative to fasting state. The recommended dosage of LIBERVANT [see Dosage and Administration (2.3)] considers the impact of food on pharmacokinetics of diazepam. As such, LIBERVANT may be administered without regard to food.

Distribution

The volume of distribution of diazepam was calculated to be approximately 1.46 L/kg. Both diazepam and its major active metabolite, desmethyldiazepam, bind extensively to plasma proteins (95%-98%).

Elimination

Metabolism

It has been reported in the literature that diazepam is extensively metabolized to one major active metabolite (desmethyldiazepam) and two minor active metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam) in plasma. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. The marked inter-individual variability in the clearance of diazepam reported in the literature is probably attributable to variability of CYP2C19 (which is known to exhibit genetic polymorphism; about 3-5% of Caucasians have little or no activity and are “poor metabolizers”) and CYP3A4. No inhibition was demonstrated in the presence of inhibitors selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that these enzymes are not significantly involved in metabolism of diazepam.

Excretion

The mean elimination half-lives of diazepam and desmethyldiazepam were found to be approximately 86 hours and 147 hours, respectively.

Specific Populations

Pediatric Patients

Literature reviews indicate that following IV administration (0.33 mg/kg), the half-life of diazepam in pediatric patients 2 to 5 years of age is approximately 15 to 21 hours.

Patients with Renal Impairment

The pharmacokinetics of diazepam have not been studied in subjects with renal impairment.

Patients with Hepatic Impairment

No pharmacokinetic studies were conducted with LIBERVANT in subjects with hepatic impairment. Literature review indicates that following administration of 0.1 to 0.15 mg/kg of diazepam intravenously, the half-life of diazepam was prolonged by two to five-fold in subjects with alcoholic cirrhosis (n=24) compared to age-matched control subjects (n=37) with a corresponding decrease in clearance by half. However, the exact degree of hepatic impairment in these subjects was not characterized in this literature.

Effect of Gender, Race, and Cigarette Smoking

No targeted pharmacokinetic studies have been conducted to evaluate the effect of gender, race, and cigarette smoking on the pharmacokinetics of diazepam. However, covariate analysis of a population of treated patients following administration of diazepam rectal gel, indicated that neither gender nor cigarette smoking had any effect on the pharmacokinetics of diazepam.

Carcinogenesis

In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately 10 and 20 times, respectively, a human dose of 0.6 mg/kg/day on a mg/m2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species.

Mutagenesis

The data currently available are inadequate to determine the mutagenic potential of diazepam.

Impairment of Fertility

Reproduction studies of diazepam in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 27 times a human dose of 0.6 mg/kg/day on a mg/m2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 22 times a human dose of 0.6 mg/kg/day on a mg/m2 basis).

Safety and effectiveness of LIBERVANT in pediatric patients 2 to 5 years of age are supported by evidence from adequate and well-controlled studies of diazepam rectal gel in adult and pediatric patients, adult bioavailability studies comparing LIBERVANT with diazepam rectal gel, adult and pediatric LIBERVANT pharmacokinetic data, and an open-label safety study of LIBERVANT including patients 2 years to 5 years of age [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "Safety and effectiveness of LIBERVANT in pediatric patients 2 to 5 years of age are supported by evidence from adequate and well-controlled studies of diazepam rectal gel in adult and pediatric patients, adult bioavailability studies comparing LIBERVANT with diazepam rectal gel, adult and pediatric LIBERVANT pharmacokinetic data, and an open-label safety study of LIBERVANT including patients 2 years to 5 years of age [see Clinical Pharmacology (12.3)].\n" }

The effectiveness of diazepam rectal gel has been established in two adequate and well-controlled clinical studies in pediatric patients 2 years of age and older and adults exhibiting intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern.

{ "type": "p", "children": [], "text": "The effectiveness of diazepam rectal gel has been established in two adequate and well-controlled clinical studies in pediatric patients 2 years of age and older and adults exhibiting intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern." }

A randomized, double-blind study compared sequential doses of diazepam rectal gel and placebo in 91 patients (47 pediatric patients 2 years of age and older, 44 adults) exhibiting the appropriate seizure profile. The first dose was given at the onset of an identified episode. Pediatric patients 2 years of age and older were dosed again 4 hours after the first dose and were observed for a total of 12 hours. Adults were dosed at 4 and 12 hours after the first dose and were observed for a total of 24 hours. Primary outcomes for this study were seizure frequency during the period of observation and a global assessment that took into account the severity and nature of the seizures as well as their frequency.

{ "type": "p", "children": [], "text": "A randomized, double-blind study compared sequential doses of diazepam rectal gel and placebo in 91 patients (47 pediatric patients 2 years of age and older, 44 adults) exhibiting the appropriate seizure profile. The first dose was given at the onset of an identified episode. Pediatric patients 2 years of age and older were dosed again 4 hours after the first dose and were observed for a total of 12 hours. Adults were dosed at 4 and 12 hours after the first dose and were observed for a total of 24 hours. Primary outcomes for this study were seizure frequency during the period of observation and a global assessment that took into account the severity and nature of the seizures as well as their frequency." }

The median seizure frequency for the diazepam rectal gel treated group was zero seizures per hour, compared to a median seizure frequency of 0.3 seizures per hour for the placebo group, a difference that was statistically significant (p <0.0001). All three categories of the global assessment (seizure frequency, seizure severity, and “overall”) were also found to be statistically significant in favor of diazepam rectal gel (p < 0.0001). The following histogram displays the results for the “overall” category of the global assessment.

{ "type": "p", "children": [], "text": "The median seizure frequency for the diazepam rectal gel treated group was zero seizures per hour, compared to a median seizure frequency of 0.3 seizures per hour for the placebo group, a difference that was statistically significant (p <0.0001). All three categories of the global assessment (seizure frequency, seizure severity, and “overall”) were also found to be statistically significant in favor of diazepam rectal gel (p < 0.0001). The following histogram displays the results for the “overall” category of the global assessment." }

Figure 1: Caregiver Overall Global Assessment of the Efficacy of Diazepam Rectal Gel

{ "type": "p", "children": [], "text": "\nFigure 1: Caregiver Overall Global Assessment of the Efficacy of Diazepam Rectal Gel\n" }

Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0002) as shown in the following graph.

{ "type": "p", "children": [], "text": "Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0002) as shown in the following graph." }

Figure 2: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - First Study

{ "type": "p", "children": [], "text": "\nFigure 2: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - First Study\n" }

In addition, 62% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 20% of placebo patients.

{ "type": "p", "children": [], "text": "In addition, 62% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 20% of placebo patients." }

Analysis of response by gender and age revealed no substantial differences between treatment in either of these subgroups. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians.

{ "type": "p", "children": [], "text": "Analysis of response by gender and age revealed no substantial differences between treatment in either of these subgroups. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians." }

A second double-blind study compared single doses of diazepam rectal gel and placebo in 114 patients (53 pediatric patients 2 years of age and older, 61 adults). The dose was given at the onset of the identified episode and patients were observed for a total of 12 hours. The primary outcome in this study was seizure frequency. The median seizure frequency for the diazepam rectal gel-treated group was 0 seizures per 12 hours, compared to a median seizure frequency of 2.0 seizures per 12 hours for the placebo group, a difference that was statistically significant (p < 0.03). Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0072) as shown in Figure 3.

{ "type": "p", "children": [], "text": "A second double-blind study compared single doses of diazepam rectal gel and placebo in 114 patients (53 pediatric patients 2 years of age and older, 61 adults). The dose was given at the onset of the identified episode and patients were observed for a total of 12 hours. The primary outcome in this study was seizure frequency. The median seizure frequency for the diazepam rectal gel-treated group was 0 seizures per 12 hours, compared to a median seizure frequency of 2.0 seizures per 12 hours for the placebo group, a difference that was statistically significant (p < 0.03). Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0072) as shown in Figure 3." }

Figure 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - Second Study

{ "type": "p", "children": [], "text": "\nFigure 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - Second Study\n" }

In addition, 55% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 34% of patients receiving placebo. Overall, caregivers judged diazepam rectal gel to be more effective than placebo (p = 0.018), based on a 10 cm visual analog scale. In addition, investigators also evaluated the effectiveness of diazepam rectal gel and judged diazepam rectal gel to be more effective than placebo (p < 0.001).

{ "type": "p", "children": [], "text": "In addition, 55% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 34% of patients receiving placebo. Overall, caregivers judged diazepam rectal gel to be more effective than placebo (p = 0.018), based on a 10 cm visual analog scale. In addition, investigators also evaluated the effectiveness of diazepam rectal gel and judged diazepam rectal gel to be more effective than placebo (p < 0.001)." }

An analysis of response by gender revealed a statistically significant difference between treatments in females but not in males in this study, and the difference between the 2 genders in response to the treatments reached borderline statistical significance. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians.

{ "type": "p", "children": [], "text": "An analysis of response by gender revealed a statistically significant difference between treatments in females but not in males in this study, and the difference between the 2 genders in response to the treatments reached borderline statistical significance. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians." }

LIBERVANT (diazepam buccal film) is supplied as five strengths of a rectangular green film imprinted in white ink according to their respective strengths and packaged in individual child-resistant polyester/foil laminated pouches (see Table 4).

<div class="scrollingtable"><table> <caption> <span>Table 4: Available Packaging Configurations</span> </caption> <colgroup> <col width="150"/> <col width="200"/> <col width="300"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule">Description</td><td align="center" class="Lrule Rrule Toprule">Contents</td><td align="center" class="Lrule Rrule Toprule">NDC</td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"> 5 mg carton</td><td align="left" class="Lrule Rrule Toprule"> 5 mg film strip imprinted with D5</td><td align="left" class="Lrule Rrule Toprule"> <p class="First"> NDC 10094-305-01 (Individual pouch)</p> <p> NDC 10094-305-02 (Carton of 2 pouches)</p> </td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"> 7.5 mg carton</td><td align="left" class="Lrule Rrule Toprule"> 7.5 mg film strip imprinted with D7●5</td><td align="left" class="Lrule Rrule Toprule"> <p class="First"> NDC 10094-307-01 (Individual pouch)</p> <p> NDC 10094-307-02 (Carton of 2 pouches)</p> </td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"> 10 mg carton</td><td align="left" class="Lrule Rrule Toprule"> 10 mg film strip imprinted with D10</td><td align="left" class="Lrule Rrule Toprule"> <p class="First"> NDC 10094-310-01 (Individual pouch)</p> <p> NDC10094-310-02 (Carton of 2 pouches)</p> </td> </tr> <tr> <td align="left" class="Lrule Rrule Toprule"> 12.5 mg carton</td><td align="left" class="Lrule Rrule Toprule"> 12.5 mg film strip imprinted with D12●5 </td><td align="left" class="Lrule Rrule Toprule"> <p class="First"> NDC 10094-312-01 (Individual pouch)</p> <p> NDC 10094-312-02 (Carton of 2 pouches)</p> </td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule Toprule"> 15 mg carton</td><td align="left" class="Lrule Rrule Toprule"> 15 mg film strip imprinted with D15</td><td align="left" class="Lrule Rrule Toprule"> <p class="First"> NDC 10094-315-01 (Individual pouch)</p> <p> NDC 10094-315-02 (Carton of 2 pouches)</p> </td> </tr> </tbody> </table></div>

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Advise the caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use)." }

Risks from Concomitant Use with Opioids

{ "type": "p", "children": [], "text": "\nRisks from Concomitant Use with Opioids\n" }

Inform caregivers that concomitant use of benzodiazepines, including LIBERVANT, and opioids may result in profound sedation, respiratory depression, coma, and death and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

{ "type": "p", "children": [], "text": "Inform caregivers that concomitant use of benzodiazepines, including LIBERVANT, and opioids may result in profound sedation, respiratory depression, coma, and death and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.1)].\n" }

Abuse, Misuse, and Addiction

{ "type": "p", "children": [], "text": "\nAbuse, Misuse, and Addiction \n" }

Inform caregivers that the use of LIBERVANT more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform caregivers about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].

{ "type": "p", "children": [], "text": "Inform caregivers that the use of LIBERVANT more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform caregivers about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].\n" }

Withdrawal Reactions

{ "type": "p", "children": [], "text": "\nWithdrawal Reactions\n" }

Inform caregivers that the use of LIBERVANT more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of LIBERVANT may precipitate acute withdrawal reactions, which can be life-threatening. Inform caregivers that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.2)].

{ "type": "p", "children": [], "text": "Inform caregivers that the use of LIBERVANT more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of LIBERVANT may precipitate acute withdrawal reactions, which can be life-threatening. Inform caregivers that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.2)].\n" }

Important Treatment Instructions

{ "type": "p", "children": [], "text": "\nImportant Treatment Instructions \n" }

Instruct caregivers on what is and is not an intermittent and stereotypic episode of increased seizure activity (i.e., seizure cluster) that is appropriate for treatment, and the timing of administration in relation to the onset of the episode.

{ "type": "p", "children": [], "text": "Instruct caregivers on what is and is not an intermittent and stereotypic episode of increased seizure activity (i.e., seizure cluster) that is appropriate for treatment, and the timing of administration in relation to the onset of the episode." }

Instruct caregivers on what to observe following administration, and what would constitute an outcome requiring immediate medical attention.

{ "type": "p", "children": [], "text": "Instruct caregivers on what to observe following administration, and what would constitute an outcome requiring immediate medical attention." }

Instruct caregivers not to administer a second dose of LIBERVANT if they are concerned by the patient’s breathing, the patient requires emergency rescue treatment with assisted breathing or intubation, or there is excessive sedation [see Use in Specific Populations (8.6)].

{ "type": "p", "children": [], "text": "Instruct caregivers not to administer a second dose of LIBERVANT if they are concerned by the patient’s breathing, the patient requires emergency rescue treatment with assisted breathing or intubation, or there is excessive sedation [see Use in Specific Populations (8.6)]." }

Advise caregivers on how frequently they can treat successive seizure cluster episodes over time.

{ "type": "p", "children": [], "text": "Advise caregivers on how frequently they can treat successive seizure cluster episodes over time." }

CNS Depression Advise caregivers to check with their healthcare provider before LIBERVANT is taken with other CNS depressants, such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "\nCNS Depression\nAdvise caregivers to check with their healthcare provider before LIBERVANT is taken with other CNS depressants, such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol [see Warnings and Precautions (5.4)]." }

If applicable, caution patients and caregivers about operating hazardous machinery, including driving a motor vehicle, or riding a bicycle, until they are reasonably certain that LIBERVANT does not affect them adversely (e.g., impair judgment, thinking or motor skills).

{ "type": "p", "children": [], "text": "If applicable, caution patients and caregivers about operating hazardous machinery, including driving a motor vehicle, or riding a bicycle, until they are reasonably certain that LIBERVANT does not affect them adversely (e.g., impair judgment, thinking or motor skills)." }

Suicidal Thinking and Behavior Counsel patients, their caregivers, and their families that AEDs, including LIBERVANT, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Caregivers should report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.5)].

{ "type": "p", "children": [], "text": "\nSuicidal Thinking and Behavior\nCounsel patients, their caregivers, and their families that AEDs, including LIBERVANT, may increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts of self-harm. Caregivers should report behaviors of concern immediately to healthcare providers [see Warnings and Precautions (5.5)]." }

Proper Administration

{ "type": "p", "children": [], "text": "\nProper Administration\n" }

Discuss the steps involved in the administration of LIBERVANT with the caregiver. The steps are described in the Medication Guide and Instruction for Use.

{ "type": "p", "children": [], "text": "\nDiscuss the steps involved in the administration of LIBERVANT with the caregiver. The steps are described in the Medication Guide and Instruction for Use.\n" }

Manufactured by:Aquestive TherapeuticsWarren, NJ

{ "type": "p", "children": [], "text": "Manufactured by:Aquestive TherapeuticsWarren, NJ" }

<div class="scrollingtable"><table> <colgroup> <col width="319"/> <col width="319"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Lrule Rrule Toprule" colspan="2"><span class="Bold">MEDICATION GUIDE</span> <br/> <span class="Bold">LIBERVANT</span><span class="Bold"><span class="Sup">™</span></span><span class="Bold">(lih-ber-vant)</span> <br/> <span class="Bold">(diazepam) </span> <br/> <span class="Bold">buccal film, C-IV</span></td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What is the most important information I should know about LIBERVANT?</span> <br/> <ul class="Disc"> <li> <span class="Bold">LIBERVANT is a benzodiazepine medicine. Taking benzodiazepines </span><span class="Bold">with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) </span><span class="Bold">can cause severe drowsiness, breathing problems (respiratory depression), coma, and death.</span> Get emergency help right away if any of the following happens: <br/> <span class="Bold">◦</span><span class="Bold"> shallow or slowed breathing,</span> <br/> <span class="Bold">◦</span><span class="Bold"> breathing stops (which may lead to the heart stopping),</span> <br/> <span class="Bold">◦</span><span class="Bold"> excessive sleepiness (sedation).</span> </li> </ul> <span class="Bold">     Do not allow your child to drive a motor vehicle, operate heavy machinery, or ride a bicycle until you know how taking LIBERVANT with opioids affects your child.</span> <br/> <ul class="Disc"> <li> <span class="Bold">Risk of abuse, misuse, and addiction.</span> LIBERVANT is used in children 2 to 5 years of age. The unapproved use of LIBERVANT has a risk for abuse, misuse, and addiction, which can lead to overdose and serious side effects including coma and death.<br/> <span class="Bold">◦ Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including diazepam (the active ingredient in LIBERVANT).</span> These serious side effects may also includedelirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <span class="Bold">Call your child’s healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. </span> <br/> <span class="Bold">◦ Your child can develop an addiction even if your child takes LIBERVANT as prescribed by your child’s healthcare provider.</span> <br/> <span class="Bold">◦ Give LIBERVANT exactly as your child’s healthcare provider prescribed.</span> <br/>◦ Do not share LIBERVANT with other people.<br/>◦  Keep LIBERVANT in a safe place and away from children.</li> <li> <span class="Bold">Physical dependence and withdrawal reactions. LIBERVANT is intended for use if needed in order to treat higher than usual seizure activity. Benzodiazepines, including</span> LIBERVANT, can cause physical dependence and withdrawal reactions, especially if used daily. LIBERVANT is not intended for daily use.<br/> <span class="Bold">◦ Do not suddenly stop giving LIBERVANT to your child without talking to your child’s healthcare provider. </span>Stopping LIBERVANT suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures that will not stop (status epilepticus), sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, homicidal thoughts, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.<span class="Bold"> Call your child’s healthcare provider or go to the nearest hospital emergency room right away if your child gets any of these symptoms.</span> <br/> <span class="Bold">◦ Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months</span> including,anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning, or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.<br/>◦Physical dependence is not the same as drug addiction. Your child’s healthcare provider can tell you more about the differences between physical dependence and drug addiction.<br/>◦ Do not give your child more LIBERVANT than prescribed or give LIBERVANT more often than prescribed.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"> <ul class="Disc"> <li> <span class="Bold">LIBERVANT can make your child sleepy or dizzy and can slow your child’s thinking and motor skills.</span> <br/>◦ Do not allow your child to drive a motor vehicle, operate machinery, or ride a bicycle until you know how LIBERVANT affects your child.<br/>◦ Do not give other drugs that may make your child sleepy or dizzy while taking LIBERVANT without first talking to your child’s healthcare provider. When taken with drugs that cause sleepiness or dizziness, LIBERVANT may make your child’s sleepiness or dizziness much worse.</li> </ul> <span class="Bold">Like other antiepileptic medicines, LIBERVANT may cause suicidal thoughts or actions in a small number of people, about 1 in 500.</span> <br/> <span class="Bold">Call a healthcare provider right away if your child has any of these symptoms, especially if they are new, worse, or worry you:</span></td> </tr> <tr> <td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>thoughts about suicide or dying</li> </ul> </td><td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>attempts to commit suicide</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>new or worse depression</li> </ul> </td><td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>new or worse anxiety or irritability      </li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>feeling agitated or restless</li> </ul> </td><td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>an extreme increase in activity and talking (mania)</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>trouble sleeping (insomnia)</li> </ul> </td><td class="Lrule Rrule"></td> </tr> <tr> <td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>acting aggressive, being angry or violent</li> </ul> </td><td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>new or worse panic attacks</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>other unusual changes in behavior or mood</li> </ul> </td><td class="Lrule Rrule Toprule"> <ul class="Disc"> <li>acting on dangerous impulses</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">How can I watch for early symptoms of suicidal thoughts or actions?</span> <br/> <ul class="Disc"> <li>Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.</li> <li>Keep all follow-up visits with your child’s healthcare provider as scheduled.</li> </ul> <span class="Bold">Call your child’s healthcare provider between visits as needed, especially if you are worried about symptoms.</span> Suicidal thoughts or actions can be caused by things other than medicines. If your child has suicidal thoughts or actions, your child’s healthcare provider may check for other causes.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What is LIBERVANT?</span> <br/> <ul class="Disc"> <li>LIBERVANT is a prescription medicine used for the short-term treatment of seizure clusters (also known as “acute repetitive seizures”) that are different from a person’s usual seizure pattern in people 2 to 5 years of age.</li> </ul> <span class="Bold">LIBERVANT is a federally controlled substance (C-IV) because it contains diazepam that can be abused or lead to dependence.</span> Keep LIBERVANT in a safe place to prevent misuse and abuse. Selling or giving away LIBERVANT may harm others and is against the law. It is not known if LIBERVANT is safe and effective in children less than 2 years of age and over 5 years of age.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Do not give LIBERVANT to your child if your child:</span> <br/> <ul class="Disc"> <li>is allergic to diazepam or any of the ingredients in LIBERVANT. See the end of this Medication Guide for a complete list of ingredients in LIBERVANT.</li> <li>has an eye problem called acute narrow angle glaucoma.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">Before you give LIBERVANT, tell your child’s healthcare provider about all of your child’s medical conditions, including if your child:</span> <br/> <ul class="Disc"> <li>has a history of depression, mood problems, or suicidal thoughts or behavior.</li> <li>has liver or kidney problems.</li> <li>has asthma, emphysema, bronchitis, chronic obstructive pulmonary disease, or other breathing problems.</li> </ul> <span class="Bold">Tell your child’s healthcare provider about all the medicines your child takes,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking LIBERVANT with certain other medicines can cause side effects or affect how well LIBERVANT or the other medicines work. Do not start or stop other medicines without talking to your child’s healthcare provider.</td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">How should I give LIBERVANT?</span> <br/> <ul class="Disc"> <li> <span class="Bold">Read the Instructions for Use that comes with this Medication Guide for detailed information about the right way to give LIBERVANT.</span> </li> <li>Give LIBERVANT exactly as your child’s healthcare provider tells you to.</li> <li>Do not change your child’s dosage unless your child’s healthcare provider tells you to change it.</li> <li>To give LIBERVANT:<br/>◦ You as the caregiver must be able to tell the difference between cluster seizures and ordinary seizures.<br/>◦ You as the caregiver must be comfortable in your ability to give LIBERVANT as instructed by your child’s healthcare provider and as instructed in the Instructions for Use at the end of this Medication Guide.<br/>◦ You as the caregiver must understand your child’s healthcare provider’s instructions about when to use LIBERVANT.</li> <li>Your child’s healthcare provider will tell you:<br/>◦ what seizure clusters are,<br/>◦ exactly how much LIBERVANT to give to your child,<br/>◦ when to give LIBERVANT,<br/>◦ how to give LIBERVANT,<br/>◦ what to do after you give LIBERVANT if the seizures do not stop or there is a change in breathing, behavior, or condition that worries you.</li> <li>Your child’s healthcare provider should show you how to give LIBERVANT the right way.</li> <li>You should carry LIBERVANT with you in case you need to give it to treat your child’s seizure clusters.</li> <li>Before a seizure cluster happens, family members, caregivers, and other people who may have to give LIBERVANT should know where you keep your LIBERVANT and how to give LIBERVANT.</li> <li>Each LIBERVANT comes in a sealed foil pouch. Do not open the foil pouch until you are ready to use it.</li> <li> <span class="Bold">Do not</span> split LIBERVANT. The entire film should be placed on the inside of the cheek.</li> <li>Allow LIBERVANT to dissolve. <span class="Bold">Do not</span> chew or swallow the film.</li> <li>Do not take with liquids.</li> <li>LIBERVANT can be taken with or without food.</li> <li> <span class="Bold">What should I do after LIBERVANT has been given:</span> <br/>◦ Note the time LIBERVANT was given and changes in the resting breathing rate.<br/>◦ Your child’s healthcare provider may prescribe a second dose of LIBERVANT.<br/>◦ If a second dose is needed, it may be given at least 4 hours after the first dose of LIBERVANT film is given.<br/>◦ Do not give more than 2 doses of LIBERVANT to treat a seizure cluster.                                                                                                                                         <br/>◦ Do not give a second dose of LIBERVANT if:</li> </ul>            ▪ you are concerned about your child’s breathing,<br/>            ▪ an emergency rescue treatment with breathing help is needed,<br/>            ▪ or there is more sleepiness than normal.<br/> <span class="Bold">Call for emergency medical help if any of the following happens:</span> <br/>      ◦ seizure behavior is different from other episodes the child has had.<br/>      ◦ you are alarmed by how often the seizure happens, by how severe it is, by how long it lasts, or seizure is alarming.<br/>      ◦ the child has unusual coloring or breathing.<br/> <ul class="Disc"> <li> <span class="Bold">Do not</span> use LIBERVANT for:<br/>◦ more than 1 seizure cluster episode every 5 days and <br/>◦ more than 5 episodes each month.</li> <li>Talk to your child’s healthcare provider about slowly stopping LIBERVANT to avoid withdrawal symptoms.</li> <li>If you give too much LIBERVANT, call your child’s healthcare provider or go to the nearest hospital emergency room right away.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What are the possible side effects of LIBERVANT?</span> <br/> <span class="Bold">LIBERVANT may cause serious side effects, including: </span> <br/> <ul class="Disc"> <li> <span class="Bold">See “What is the most important information I should know about LIBERVANT?”</span> </li> </ul> <span class="Bold">The most common side effects of LIBERVANT are:</span> <br/> <ul class="Disc"> <li>sleepiness</li> <li>headache</li> </ul> <p class="First">These are not all the possible side effects of LIBERVANT.</p> <p> <br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">How should I store LIBERVANT?</span> <ul class="Disc"> <li>Store LIBERVANT at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Keep LIBERVANT in the foil pouch until ready to use.</li> <li> <span class="Bold">Keep LIBERVANT and all medicines out of the reach of children.</span> </li> </ul> </td> </tr> <tr> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">General information about the safe and effective use of LIBERVANT.</span> <br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LIBERVANT for a condition for which it was not prescribed. Do not give LIBERVANT to other people, even if they have the same symptoms that your child has. It may harm them.<br/>You can ask your pharmacist or healthcare provider for information about LIBERVANT that is written for health professionals.</td> </tr> <tr class="Last"> <td class="Lrule Rrule Toprule" colspan="2"><span class="Bold">What are the ingredients in LIBERVANT?</span> <br/> <span class="Bold">Active ingredient: </span>diazepam<br/> <span class="Bold">Inactive ingredients: </span>benzyl alcohol, clove oil, EDTA disodium salt, FD&amp;C Green #3, glycerol monooleate, hypromellose, peppermint oil, polyethylene oxide, polyvinylpyrrolidone, sodium phosphate, sucralose, vanillin, xanthan gum, water, and white ink<br/>Manufactured by: Aquestive Therapeutics, Warren NJ 07059, USA<br/>For more information, go to www.aquestive.com or call 1-877-394-5045.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table>\n<colgroup>\n<col width=\"319\"/>\n<col width=\"319\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">MEDICATION GUIDE</span>\n<br/>\n<span class=\"Bold\">LIBERVANT</span><span class=\"Bold\"><span class=\"Sup\">™</span></span><span class=\"Bold\">(lih-ber-vant)</span>\n<br/>\n<span class=\"Bold\">(diazepam) </span>\n<br/>\n<span class=\"Bold\">buccal film, C-IV</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What is the most important information I should know about LIBERVANT?</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">LIBERVANT is a benzodiazepine medicine. Taking benzodiazepines </span><span class=\"Bold\">with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) </span><span class=\"Bold\">can cause severe drowsiness, breathing problems (respiratory depression), coma, and death.</span> Get emergency help right away if any of the following happens: <br/>\n<span class=\"Bold\">◦</span><span class=\"Bold\"> shallow or slowed breathing,</span>\n<br/>\n<span class=\"Bold\">◦</span><span class=\"Bold\"> breathing stops (which may lead to the heart stopping),</span>\n<br/>\n<span class=\"Bold\">◦</span><span class=\"Bold\"> excessive sleepiness (sedation).</span>\n</li>\n</ul>\n<span class=\"Bold\">     Do not allow your child to drive a motor vehicle, operate heavy machinery, or ride a bicycle until you know how taking LIBERVANT with opioids affects your child.</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Risk of abuse, misuse, and addiction.</span> LIBERVANT is used in children 2 to 5 years of age. The unapproved use of LIBERVANT has a risk for abuse, misuse, and addiction, which can lead to overdose and serious side effects including coma and death.<br/>\n<span class=\"Bold\">◦ Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including diazepam (the active ingredient in LIBERVANT).</span> These serious side effects may also includedelirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <span class=\"Bold\">Call your child’s healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. </span>\n<br/>\n<span class=\"Bold\">◦ Your child can develop an addiction even if your child takes LIBERVANT as prescribed by your child’s healthcare provider.</span>\n<br/>\n<span class=\"Bold\">◦ Give LIBERVANT exactly as your child’s healthcare provider prescribed.</span>\n<br/>◦ Do not share LIBERVANT with other people.<br/>◦  Keep LIBERVANT in a safe place and away from children.</li>\n<li>\n<span class=\"Bold\">Physical dependence and withdrawal reactions. LIBERVANT is intended for use if needed in order to treat higher than usual seizure activity. Benzodiazepines, including</span> LIBERVANT, can cause physical dependence and withdrawal reactions, especially if used daily. LIBERVANT is not intended for daily use.<br/>\n<span class=\"Bold\">◦ Do not suddenly stop giving LIBERVANT to your child without talking to your child’s healthcare provider. </span>Stopping LIBERVANT suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures that will not stop (status epilepticus), sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, homicidal thoughts, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.<span class=\"Bold\"> Call your child’s healthcare provider or go to the nearest hospital emergency room right away if your child gets any of these symptoms.</span>\n<br/>\n<span class=\"Bold\">◦ Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months</span> including,anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning, or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.<br/>◦Physical dependence is not the same as drug addiction. Your child’s healthcare provider can tell you more about the differences between physical dependence and drug addiction.<br/>◦ Do not give your child more LIBERVANT than prescribed or give LIBERVANT more often than prescribed.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">LIBERVANT can make your child sleepy or dizzy and can slow your child’s thinking and motor skills.</span>\n<br/>◦ Do not allow your child to drive a motor vehicle, operate machinery, or ride a bicycle until you know how LIBERVANT affects your child.<br/>◦ Do not give other drugs that may make your child sleepy or dizzy while taking LIBERVANT without first talking to your child’s healthcare provider. When taken with drugs that cause sleepiness or dizziness, LIBERVANT may make your child’s sleepiness or dizziness much worse.</li>\n</ul>\n<span class=\"Bold\">Like other antiepileptic medicines, LIBERVANT may cause suicidal thoughts or actions in a small number of people, about 1 in 500.</span>\n<br/>\n<span class=\"Bold\">Call a healthcare provider right away if your child has any of these symptoms, especially if they are new, worse, or worry you:</span></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>thoughts about suicide or dying</li>\n</ul>\n</td><td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>attempts to commit suicide</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>new or worse depression</li>\n</ul>\n</td><td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>new or worse anxiety or irritability      </li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>feeling agitated or restless</li>\n</ul>\n</td><td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>an extreme increase in activity and talking (mania)</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>trouble sleeping (insomnia)</li>\n</ul>\n</td><td class=\"Lrule Rrule\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>acting aggressive, being angry or violent</li>\n</ul>\n</td><td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>new or worse panic attacks</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>other unusual changes in behavior or mood</li>\n</ul>\n</td><td class=\"Lrule Rrule Toprule\">\n<ul class=\"Disc\">\n<li>acting on dangerous impulses</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">How can I watch for early symptoms of suicidal thoughts or actions?</span>\n<br/>\n<ul class=\"Disc\">\n<li>Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.</li>\n<li>Keep all follow-up visits with your child’s healthcare provider as scheduled.</li>\n</ul>\n<span class=\"Bold\">Call your child’s healthcare provider between visits as needed, especially if you are worried about symptoms.</span> Suicidal thoughts or actions can be caused by things other than medicines. If your child has suicidal thoughts or actions, your child’s healthcare provider may check for other causes.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What is LIBERVANT?</span>\n<br/>\n<ul class=\"Disc\">\n<li>LIBERVANT is a prescription medicine used for the short-term treatment of seizure clusters (also known as “acute repetitive seizures”) that are different from a person’s usual seizure pattern in people 2 to 5 years of age.</li>\n</ul>\n<span class=\"Bold\">LIBERVANT is a federally controlled substance (C-IV) because it contains diazepam that can be abused or lead to dependence.</span> Keep LIBERVANT in a safe place to prevent misuse and abuse. Selling or giving away LIBERVANT may harm others and is against the law. It is not known if LIBERVANT is safe and effective in children less than 2 years of age and over 5 years of age.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Do not give LIBERVANT to your child if your child:</span>\n<br/>\n<ul class=\"Disc\">\n<li>is allergic to diazepam or any of the ingredients in LIBERVANT. See the end of this Medication Guide for a complete list of ingredients in LIBERVANT.</li>\n<li>has an eye problem called acute narrow angle glaucoma.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">Before you give LIBERVANT, tell your child’s healthcare provider about all of your child’s medical conditions, including if your child:</span>\n<br/>\n<ul class=\"Disc\">\n<li>has a history of depression, mood problems, or suicidal thoughts or behavior.</li>\n<li>has liver or kidney problems.</li>\n<li>has asthma, emphysema, bronchitis, chronic obstructive pulmonary disease, or other breathing problems.</li>\n</ul>\n<span class=\"Bold\">Tell your child’s healthcare provider about all the medicines your child takes,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking LIBERVANT with certain other medicines can cause side effects or affect how well LIBERVANT or the other medicines work. Do not start or stop other medicines without talking to your child’s healthcare provider.</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">How should I give LIBERVANT?</span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Read the Instructions for Use that comes with this Medication Guide for detailed information about the right way to give LIBERVANT.</span>\n</li>\n<li>Give LIBERVANT exactly as your child’s healthcare provider tells you to.</li>\n<li>Do not change your child’s dosage unless your child’s healthcare provider tells you to change it.</li>\n<li>To give LIBERVANT:<br/>◦ You as the caregiver must be able to tell the difference between cluster seizures and ordinary seizures.<br/>◦ You as the caregiver must be comfortable in your ability to give LIBERVANT as instructed by your child’s healthcare provider and as instructed in the Instructions for Use at the end of this Medication Guide.<br/>◦ You as the caregiver must understand your child’s healthcare provider’s instructions about when to use LIBERVANT.</li>\n<li>Your child’s healthcare provider will tell you:<br/>◦ what seizure clusters are,<br/>◦ exactly how much LIBERVANT to give to your child,<br/>◦ when to give LIBERVANT,<br/>◦ how to give LIBERVANT,<br/>◦ what to do after you give LIBERVANT if the seizures do not stop or there is a change in breathing, behavior, or condition that worries you.</li>\n<li>Your child’s healthcare provider should show you how to give LIBERVANT the right way.</li>\n<li>You should carry LIBERVANT with you in case you need to give it to treat your child’s seizure clusters.</li>\n<li>Before a seizure cluster happens, family members, caregivers, and other people who may have to give LIBERVANT should know where you keep your LIBERVANT and how to give LIBERVANT.</li>\n<li>Each LIBERVANT comes in a sealed foil pouch. Do not open the foil pouch until you are ready to use it.</li>\n<li>\n<span class=\"Bold\">Do not</span> split LIBERVANT. The entire film should be placed on the inside of the cheek.</li>\n<li>Allow LIBERVANT to dissolve. <span class=\"Bold\">Do not</span> chew or swallow the film.</li>\n<li>Do not take with liquids.</li>\n<li>LIBERVANT can be taken with or without food.</li>\n<li>\n<span class=\"Bold\">What should I do after LIBERVANT has been given:</span>\n<br/>◦ Note the time LIBERVANT was given and changes in the resting breathing rate.<br/>◦ Your child’s healthcare provider may prescribe a second dose of LIBERVANT.<br/>◦ If a second dose is needed, it may be given at least 4 hours after the first dose of LIBERVANT film is given.<br/>◦ Do not give more than 2 doses of LIBERVANT to treat a seizure cluster.                                                                                                                                         <br/>◦ Do not give a second dose of LIBERVANT if:</li>\n</ul>            ▪ you are concerned about your child’s breathing,<br/>            ▪ an emergency rescue treatment with breathing help is needed,<br/>            ▪ or there is more sleepiness than normal.<br/>\n<span class=\"Bold\">Call for emergency medical help if any of the following happens:</span>\n<br/>      ◦ seizure behavior is different from other episodes the child has had.<br/>      ◦ you are alarmed by how often the seizure happens, by how severe it is, by how long it lasts, or seizure is alarming.<br/>      ◦ the child has unusual coloring or breathing.<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Do not</span> use LIBERVANT for:<br/>◦ more than 1 seizure cluster episode every 5 days and <br/>◦ more than 5 episodes each month.</li>\n<li>Talk to your child’s healthcare provider about slowly stopping LIBERVANT to avoid withdrawal symptoms.</li>\n<li>If you give too much LIBERVANT, call your child’s healthcare provider or go to the nearest hospital emergency room right away.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What are the possible side effects of LIBERVANT?</span>\n<br/>\n<span class=\"Bold\">LIBERVANT may cause serious side effects, including: </span>\n<br/>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">See “What is the most important information I should know about LIBERVANT?”</span>\n</li>\n</ul>\n<span class=\"Bold\">The most common side effects of LIBERVANT are:</span>\n<br/>\n<ul class=\"Disc\">\n<li>sleepiness</li>\n<li>headache</li>\n</ul>\n<p class=\"First\">These are not all the possible side effects of LIBERVANT.</p>\n<p>\n<br/>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">How should I store LIBERVANT?</span>\n<ul class=\"Disc\">\n<li>Store LIBERVANT at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Keep LIBERVANT in the foil pouch until ready to use.</li>\n<li>\n<span class=\"Bold\">Keep LIBERVANT and all medicines out of the reach of children.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">General information about the safe and effective use of LIBERVANT.</span>\n<br/>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use LIBERVANT for a condition for which it was not prescribed. Do not give LIBERVANT to other people, even if they have the same symptoms that your child has. It may harm them.<br/>You can ask your pharmacist or healthcare provider for information about LIBERVANT that is written for health professionals.</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Lrule Rrule Toprule\" colspan=\"2\"><span class=\"Bold\">What are the ingredients in LIBERVANT?</span>\n<br/>\n<span class=\"Bold\">Active ingredient: </span>diazepam<br/>\n<span class=\"Bold\">Inactive ingredients: </span>benzyl alcohol, clove oil, EDTA disodium salt, FD&amp;C Green #3, glycerol monooleate, hypromellose, peppermint oil, polyethylene oxide, polyvinylpyrrolidone, sodium phosphate, sucralose, vanillin, xanthan gum, water, and white ink<br/>Manufactured by: Aquestive Therapeutics, Warren NJ 07059, USA<br/>For more information, go to www.aquestive.com or call 1-877-394-5045.</td>\n</tr>\n</tbody>\n</table></div>" }

This Medication Guide is approved by the U.S. Food and Drug Administration        Revision Date: 4/2024

{ "type": "p", "children": [], "text": "This Medication Guide is approved by the U.S. Food and Drug Administration        Revision Date: 4/2024" }

INSTRUCTIONS FOR USE

{ "type": "p", "children": [], "text": "\nINSTRUCTIONS FOR USE\n" }

LIBERVANT™ [lih-ber-vant] (diazepam) buccal film

{ "type": "p", "children": [], "text": "\nLIBERVANT™ [lih-ber-vant]\n(diazepam) buccal film\n" }

Family members, caregivers, and others who may need to administer LIBERVANT should read this Instructions for Use that comes with LIBERVANT before using it.

{ "type": "p", "children": [], "text": "Family members, caregivers, and others who may need to administer LIBERVANT should read this Instructions for Use that comes with LIBERVANT before using it." }

This Instructions for Use contains information on how to use LIBERVANT. This information does not take the place of talking to your child’s healthcare provider about your child’s medical condition or your child’s treatment. Ask your child’s healthcare provider or pharmacist if you or others who may need to administer LIBERVANT have any questions about how to use LIBERVANT the right way.

{ "type": "p", "children": [], "text": "This Instructions for Use contains information on how to use LIBERVANT. This information does not take the place of talking to your child’s healthcare provider about your child’s medical condition or your child’s treatment. Ask your child’s healthcare provider or pharmacist if you or others who may need to administer LIBERVANT have any questions about how to use LIBERVANT the right way." }

Important Information You Need to Know Before Using LIBERVANT

{ "type": "p", "children": [], "text": "\nImportant Information You Need to Know Before Using LIBERVANT\n" }

{ "type": "ul", "children": [ "For buccal use (place film on inside of cheek)", "Before using LIBERVANT, make sure your child’s healthcare provider shows you the right way to use it. If treatment is unable to be given and there is concern, call for emergency medical help right away.\n" ], "text": "" }

Preparing to Use LIBERVANT

{ "type": "p", "children": [], "text": "\nPreparing to Use LIBERVANT\n" }

{ "type": "ul", "children": [ "Make sure hands are clean and dry before handling LIBERVANT so the film does not stick to your fingers.", "Check expiration date. Do not use if the expiration date has passed." ], "text": "" }

Using LIBERVANT

{ "type": "p", "children": [], "text": "\nUsing LIBERVANT\n" }

Step 1. Open Pouch and Remove Film from Pouch

{ "type": "p", "children": [], "text": "\nStep 1. Open Pouch and Remove Film from Pouch\n" }

{ "type": "ul", "children": [ "Fold foil pouch along solid line. While folded over, note where the vertical slit is and carefully tear down the side of the pouch at the slit along the arrow to open the pouch.", "Remove LIBERVANT film from foil pouch. Each foil pouch contains 1 dose of LIBERVANT." ], "text": "" }

Step 2. Place 1 Film on Inside of Cheek

{ "type": "p", "children": [], "text": "\nStep 2. Place 1 Film on Inside of Cheek\n" }

{ "type": "ul", "children": [ "\nDo not give LIBERVANT film with liquids.\n", "Stretch either cheek open with one hand and place one film flat against the cheek with your other hand. Do not rub the film into the cheek with your finger.", "Place the film directly onto the inside of the cheek. Do not place film on teeth.", "Remove fingers from the cheek.", "\nIf the film is spit out or blown out immediately, attempt to give another dose using a new film. If you cannot give the dose, call for emergency help.\n" ], "text": "" }

Step 3. Allow Film to Dissolve

{ "type": "p", "children": [], "text": "\nStep 3. Allow Film to Dissolve\n" }

{ "type": "ul", "children": [ "\nIf the film is accidentally swallowed or chewed, there is no need to give a replacement dose.\n", "LIBERVANT will stick to the inside of the cheek and begin to dissolve.", "The mouth can be closed or remain open while waiting.", "Saliva may be swallowed normally as the film dissolves." ], "text": "" }

What to do after LIBERVANT has been taken:

{ "type": "p", "children": [], "text": "\nWhat to do after LIBERVANT has been taken:\n" }

{ "type": "ul", "children": [ "Note the time LIBERVANT was taken and changes in the resting breath rate.", "Your child’s healthcare provider may prescribe a second dose of LIBERVANT. If a second dose is needed, it may be given at least 4 hours after the first dose of LIBERVANT film is given. Repeat Steps 1 through 3.", "\nDo not give a second dose if: ◦ you are concerned about your child’s breathing,◦ an emergency rescue treatment with breathing help is needed,◦ or there is more sleepiness than normal.", "\nCall for emergency medical help if any of the following occur:◦ there is an increase in seizure frequency that does not stop after using LIBERVANT as instructed by your child’s healthcare provider◦ seizure behavior is different from other episodes◦ the frequency or severity of the seizure is alarming◦ either skin color or breathing is alarming" ], "text": "" }

Disposing of LIBERVANT

{ "type": "p", "children": [], "text": "\nDisposing of LIBERVANT\n" }

{ "type": "ul", "children": [ "Throw away (dispose of) empty foil pouch with the regular trash. Any films that were spit out or not used after opening should be flushed down the toilet or placed in the sink and rinsed with water until film is no longer visible." ], "text": "" }

For more information about LIBERVANT, go to www.aquestive.com or call 1-877-394-5045.

{ "type": "p", "children": [], "text": "For more information about LIBERVANT, go to www.aquestive.com or call 1-877-394-5045." }

Manufactured by:Aquestive TherapeuticsWarren, NJ 07059

{ "type": "p", "children": [], "text": "Manufactured by:Aquestive TherapeuticsWarren, NJ 07059" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration             Issued Date: 4/2024

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration             Issued Date: 4/2024" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-305-01Libervant(diazepam) buccal film5 mg1 Buccal Film Dose 

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-305-01Libervant(diazepam) buccal film5 mg1 Buccal Film Dose " }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-305-02Libervant(diazepam) buccal film5 mg2 Pouches

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-305-02Libervant(diazepam) buccal film5 mg2 Pouches " }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-307-01Libervant(diazepam) buccal film7.5 mg1 Buccal Film Dose

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-307-01Libervant(diazepam) buccal film7.5 mg1 Buccal Film Dose" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-307-02Libervant(diazepam) buccal film7.5 mg2 Pouches

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-307-02Libervant(diazepam) buccal film7.5 mg2 Pouches " }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-310-01Libervant(diazepam) buccal film10 mg1 Buccal Film Dose

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-310-01Libervant(diazepam) buccal film10 mg1 Buccal Film Dose" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-310-02Libervant(diazepam) buccal film10 mg2 Pouches

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-310-02Libervant(diazepam) buccal film10 mg2 Pouches " }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-312-01Libervant(diazepam) buccal film12.5 mg1 Buccal Film Dose

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-312-01Libervant(diazepam) buccal film12.5 mg1 Buccal Film Dose" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-312-02Libervant(diazepam) buccal film12.5 mg2 Pouches

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-312-02Libervant(diazepam) buccal film12.5 mg2 Pouches " }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-315-01Libervant(diazepam) buccal film15 mg1 Buccal Film Dose

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-315-01Libervant(diazepam) buccal film15 mg1 Buccal Film Dose" }

PRINCIPAL DISPLAY PANEL

{ "type": "p", "children": [], "text": "\nPRINCIPAL DISPLAY PANEL\n" }

Rx OnlyNDC 10094-315-02Libervant(diazepam) buccal film15 mg2 Pouches

{ "type": "p", "children": [], "text": "Rx OnlyNDC 10094-315-02Libervant(diazepam) buccal film15 mg2 Pouches" }

VALTOCO® is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy 2 years of age and older.

{ "type": "p", "children": [], "text": "\nVALTOCO® is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy 2 years of age and older.\n" }

Prior to treatment, healthcare professionals should instruct the individual administering VALTOCO on how to identify seizure clusters and use the product appropriately [see Dosage and Administration (2.3) and Patient Counseling Information (17)].

The recommended dose of VALTOCO nasal spray is 0.2 mg/kg to 0.5 mg/kg, depending on the patient's age and weight. See Table 1 and Table 2 for specific recommendations.

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 1: Recommended Dose Based on Age</span> </caption> <col align="left" valign="bottom" width="40%"/> <col align="left" valign="bottom" width="60%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule"><span class="XmChange">Age (Years)</span></th><th align="left" class="Rrule">Recommended Dose</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule"><span class="XmChange">2 through 5</span></td><td align="left" class="Rrule">0.5 mg/kg</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule"><span class="XmChange">6 through 11</span></td><td align="left" class="Rrule">0.3 mg/kg</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule"><span class="XmChange">12 and older</span></td><td align="left" class="Rrule">0.2 mg/kg</td> </tr> </tbody> </table></div>

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 2: Recommended Dosage and Administration for Adults and Pediatric Patients 2 Years of Age and Older</span> </caption> <col align="center" valign="top" width="16%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="10%"/> <col align="center" valign="top" width="18%"/> <col align="center" valign="top" width="20%"/> <thead> <tr class="Botrule First"> <th align="center" class="Lrule Rrule" colspan="4"><span class="XmChange">Dose Based on Age and Weight</span></th><th align="left" class="Rrule" colspan="2">Administration</th> </tr> <tr class="Botrule"> <th align="center" class="Lrule Rrule"><span class="XmChange">2 to 5 Years of Age<br/>(0.5 mg/kg)</span></th><th align="center" class="Rrule">6 to 11 Years of Age<br/>(0.3 mg/kg)</th><th align="center" class="Rrule">12 Years of Age and Older<br/>(0.2 mg/kg)</th><th align="center" class="Rrule">Dose (mg)</th><th align="center" class="Rrule">Number of Nasal Spray Devices</th><th align="center" class="Rrule">Number of Sprays</th> </tr> <tr class="Last"> <th align="left" class="Lrule Rrule" colspan="3" valign="bottom"><span class="XmChange">Weight (kg)</span></th><th align="center" class="Rrule" colspan="3"></th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule"><span class="XmChange">6 to 11</span></td><td align="center" class="Rrule">10 to 18</td><td align="center" class="Rrule">14 to 27</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">One 5 mg device</td><td align="center" class="Rrule">One spray in one nostril</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="XmChange">12 to 22</span></td><td align="center" class="Rrule">19 to 37</td><td align="center" class="Rrule">28 to 50</td><td align="center" class="Rrule">10</td><td align="center" class="Rrule">One 10 mg device</td><td align="center" class="Rrule">One spray in one nostril</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="XmChange">23 to 33</span></td><td align="center" class="Rrule">38 to 55</td><td align="center" class="Rrule">51 to 75</td><td align="center" class="Rrule">15</td><td align="center" class="Rrule">Two 7.5 mg devices</td><td align="center" class="Rrule">One spray in each nostril</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule"><span class="XmChange"> </span></td><td align="center" class="Rrule">56 to 74</td><td align="center" class="Rrule">76 and up</td><td align="center" class="Rrule">20</td><td align="center" class="Rrule">Two 10 mg devices</td><td align="center" class="Rrule">One spray in each nostril</td> </tr> </tbody> </table></div>

Second Dose (if needed): A second dose, when required, may be administered after at least 4 hours after the initial dose. If the second dose is to be administered, use a new blister pack of VALTOCO.

Maximum Dosage and Treatment Frequency: Do not use more than 2 doses of VALTOCO to treat a single episode.

Do not use VALTOCO to treat more than one episode every five days or more than five episodes per month.

VALTOCO is for intranasal use only.

No device assembly is required. VALTOCO nasal spray delivers its entire contents upon activation. Do not prime or attempt to use for more than one administration per device.

Patients and caregivers should be counseled to read carefully the "Instructions for Use" for complete directions on how to properly administer VALTOCO.

VALTOCO is available in 5 mg, 7.5 mg, and 10 mg strengths. Each VALTOCO nasal spray device contains 0.1 mL solution.

{ "type": "p", "children": [], "text": "VALTOCO is available in 5 mg, 7.5 mg, and 10 mg strengths. Each VALTOCO nasal spray device contains 0.1 mL solution." }

VALTOCO nasal spray is contraindicated in patients with:

{ "type": "p", "children": [], "text": "VALTOCO nasal spray is contraindicated in patients with:" }

{ "type": "ul", "children": [ "Known hypersensitivity to diazepam ", "Acute narrow angle glaucoma [see Warnings and Precautions (5.6)]\n" ], "text": "" }

Concomitant use of benzodiazepines, including VALTOCO, and opioids may result in profound sedation, respiratory depression, coma, and death [see Drug Interactions (7.1)]. 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 VALTOCO 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 both patients and caregivers about the risks of respiratory depression and sedation when VALTOCO is used with opioids.

The use of benzodiazepines, including VALTOCO, 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)].

Before prescribing VALTOCO and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. Use of VALTOCO, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of VALTOCO along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO (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 VALTOCO 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 VALTOCO, 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)].

Benzodiazepines, including VALTOCO, produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness (e.g., 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 VALTOCO is indicated for use solely on an intermittent basis, the potential for synergistic CNS-depressant effects 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.

Antiepileptic drugs (AEDs), including VALTOCO, 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 3 shows absolute and relative risk by indication for all evaluated AEDs.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 3: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</span> </caption> <col align="left" valign="middle" width="12%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="middle" width="19%"/> <col align="center" valign="middle" width="23%"/> <col align="center" valign="middle" width="26%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Indication</th><th align="center" class="Rrule">Placebo Patients with Events/1000 Patients</th><th align="center" class="Rrule">Drug Patients with Events per 1000 Patients</th><th align="center" class="Rrule">Relative Risk: Incidence of Drug Events in Drug Patients /Incidence in Placebo Patients</th><th align="center" class="Rrule">Risk Difference: Additional Drug Patients with Events per 1000 Patients</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Epilepsy</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">3.4</td><td align="center" class="Rrule">3.5</td><td align="center" class="Rrule">2.4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Psychiatric</td><td align="center" class="Rrule">5.7</td><td align="center" class="Rrule">8.5</td><td align="center" class="Rrule">1.5</td><td align="center" class="Rrule">2.9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Other</td><td align="center" class="Rrule">1.0</td><td align="center" class="Rrule">1.8</td><td align="center" class="Rrule">1.9</td><td align="center" class="Rrule">0.9</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Total</td><td align="center" class="Rrule">2.4</td><td align="center" class="Rrule">4.3</td><td align="center" class="Rrule">1.8</td><td align="center" class="Rrule">1.9</td> </tr> </tbody> </table></div>

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 VALTOCO 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.

Benzodiazepines, including VALTOCO, can increase intraocular pressure in patients with glaucoma. VALTOCO may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma.

Use of VALTOCO 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 VALTOCO during pregnancy or labor for signs of sedation and monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal; manage these neonates accordingly.

VALTOCO 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 VALTOCO. 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 (VALTOCO contains 10.5 mg of benzyl alcohol per 0.1 mL) [see Use in Specific Populations (8.4)].

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of VALTOCO is supported by clinical trials using diazepam rectal gel, as well as open-label, repeat-dose studies of VALTOCO in healthy subjects and epilepsy patients.

Diazepam Rectal Gel

In studies previously conducted with diazepam rectal gel, adverse event data were collected from double-blind, placebo-controlled studies and open-label studies. The majority of adverse events were mild to moderate in severity and transient in nature.

Two patients who received diazepam rectal gel died seven to 15 weeks following treatment; neither of these deaths was deemed related to diazepam rectal gel.

The most frequent adverse reactions (at least 4%) in the two double-blind, placebo-controlled studies were somnolence, headache, and diarrhea. Adverse events were usually mild or moderate in intensity.

Approximately 1.4% of the 573 patients who received diazepam rectal gel in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse reaction most frequently associated with discontinuation (occurring in three patients) was somnolence. Other adverse reactions most commonly associated with discontinuation and occurring in two patients were hypoventilation and rash. Adverse reactions associated with discontinuation occurring in one patient were asthenia, hyperkinesia, incoordination, vasodilatation, and urticaria.

In the two double-blind, placebo-controlled, parallel-group studies [see Clinical Studies (14)], the proportion of patients who discontinued treatment because of adverse events was 2% for the group treated with diazepam rectal gel, versus 2% for the placebo group. In the diazepam rectal gel group, one patient discontinued because of rash and one patient discontinued because of lethargy.

<div class="scrollingtable"><table width="60%"> <caption> <span>Table 4: Adverse Reactions That Occurred in Greater Than 1% Of Patients in Parallel-Group, Placebo-Controlled Trials with Diazepam Rectal Gel and More Common Than Placebo</span> </caption> <col align="left" valign="bottom" width="35%"/> <col align="center" valign="bottom" width="45%"/> <col align="center" valign="bottom" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">Diazepam Rectal Gel<br/> N=101<br/>%</th><th align="center" class="Rrule">Placebo<br/> N=104<br/> %</th> </tr> </thead> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule">Somnolence</td><td align="center" class="Rrule">23</td><td align="center" class="Rrule">8</td> </tr> <tr> <td align="left" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">4</td> </tr> <tr> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Lrule Rrule">Ataxia</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">&lt;1</td> </tr> <tr> <td align="left" class="Lrule Rrule">Dizziness</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td> </tr> <tr> <td align="left" class="Lrule Rrule">Euphoria</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0</td> </tr> <tr> <td align="left" class="Lrule Rrule">Incoordination</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0</td> </tr> <tr> <td align="left" class="Lrule Rrule">Rash</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">0</td> </tr> <tr> <td align="left" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td> </tr> <tr> <td align="left" class="Lrule Rrule">Asthma</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Vasodilation</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">0</td> </tr> </tbody> </table></div>

VALTOCO (Diazepam Nasal Spray)

Clinical studies of patients with epilepsy 2 years of age and older were conducted to support the safety and tolerability of VALTOCO for the treatment of acute repetitive seizures. A total of 255 patients 2 years of age and older received VALTOCO, of whom 143 received VALTOCO for at least 1 year. Other than adverse reactions related to local nasal administration, the adverse reactions reported in these studies were similar to those seen in the efficacy trials of diazepam rectal gel.

The most common local adverse reactions that occurred in at least 1% of VALTOCO-treated patients were nasal discomfort (5%), dysgeusia (2%), epistaxis (2%), and rhinorrhea (1%).

Other Adverse Reactions

Diazepam rectal gel has previously been administered to 573 patients with epilepsy during all clinical trials, only some of which were placebo-controlled. All of the events listed below occurred in at least 1% of the 573 individuals exposed to diazepam rectal gel.

Body as a Whole: Asthenia

Cardiovascular: Hypotension, vasodilatation

Nervous: Agitation, confusion, convulsion, dysarthria, emotional lability, speech disorder, thinking abnormal, vertigo

Respiratory: Hiccup

The following infrequent adverse events have been reported previously with diazepam use: depression, slurred speech, syncope, changes in libido, urinary retention, bradycardia, cardiovascular collapse, nystagmus, urticaria, neutropenia, and jaundice.

Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported with other diazepam products. If these events occur with the use of VALTOCO, the prescriber should consider discontinuation of use.

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA-A sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists [see Warnings and Precautions (5.1)]. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

Coadministration of other CNS depressants (e.g., valproate) or consumption of alcohol may potentiate the CNS-depressant effects of diazepam [see Warnings and Precautions (5.4)].

Potential interactions may occur when diazepam is given concurrently with agents that affect CYP2C19 and CYP3A4 activity.

Inhibitors of CYP2C19 and CYP3A4

Inhibitors of CYP2C19 (e.g., cimetidine, quinidine, and tranylcypromine) and CYP3A4 (e.g., ketoconazole, troleandomycin, and clotrimazole) could decrease the rate of diazepam elimination; therefore, adverse reactions to VALTOCO may be increased.

Inducers of CYP2C19 and CYP3A4

Inducers of CYP2C19 (e.g., rifampin) and CYP3A4 (e.g., carbamazepine, phenytoin, dexamethasone, and phenobarbital) could increase the rate of diazepam elimination; therefore, efficacy of VALTOCO may be decreased.

Diazepam is a substrate for CYP2C19 and CYP3A4; therefore, it is possible that VALTOCO may interfere with the metabolism of drugs which are substrates for CYP2C19 (e.g., omeprazole, propranolol, and imipramine) and CYP3A4 (e.g., cyclosporine, paclitaxel, theophylline, and warfarin) leading to a potential drug-drug interaction.

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as VALTOCO, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women who are taking VALTOCO during pregnancy enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.7) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Human Data).

In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Animal Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to VALTOCO during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.7)].

Data

Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings.

Animal Data

Diazepam has been shown to produce increased incidences of fetal malformations in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately 13 times the maximum recommended human dose [MRHD = 0.6mg/kg/day] or greater on a mg/m2 basis). Cleft palate and exencephaly are the most common and consistently reported malformations produced in these species by administration of high, maternally-toxic doses of diazepam during organogenesis.

In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic inhibition to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development that takes place during the third trimester of pregnancy in humans.

Risk Summary

Diazepam is excreted in human milk.

There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data to assess the effects of diazepam and/or its active metabolite(s) on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VALTOCO nasal spray and any potential adverse effects on the breastfed infant from VALTOCO or from the underlying maternal condition.

Clinical Considerations

Infants exposed to VALTOCO through breast milk should be monitored for sedation, poor feeding and poor weight gain.

Safety and effectiveness of VALTOCO have been established in pediatric patients 2 years to 16 years of age. Use of VALTOCO in this age group is supported by evidence from adequate and well-controlled studies of diazepam rectal gel in adult and pediatric patients, adult bioavailability studies comparing VALTOCO with diazepam rectal gel, patient pharmacokinetic data, and open-label safety studies of VALTOCO including patients 2 years to 16 years of age [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness of VALTOCO in pediatric patients below the age of 2 years have not been established.

VALTOCO is not approved for use in neonates or infants.

Clinical studies of VALTOCO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Therefore, in elderly patients, VALTOCO should be used with caution because of an increase in half-life with a corresponding decrease in the clearance of free diazepam [see Clinical Pharmacology (12.3)]. It is also recommended that the dosage be decreased to reduce the likelihood of ataxia or oversedation.

VALTOCO should be used with caution in patients with compromised respiratory function related to a concurrent disease process (e.g., asthma, pneumonia) or neurologic damage.

VALTOCO contains diazepam, a Schedule IV controlled substance.

VALTOCO is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

In the clinical studies with VALTOCO at recommended doses, abuse-related adverse events included euphoria, somnolence, sedation, anterograde amnesia, depression, anxiety, hallucinations, and restlessness.

Physical Dependence After Use of VALTOCO More Frequently Than Recommended

VALTOCO may produce physical dependence if used more frequently than recommended. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Although VALTOCO 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 or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO [see Warnings and Precautions (5.3)].

Acute Withdrawal Signs and Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to VALTOCO may develop after use more frequently than recommended. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

It is recommended that patients be treated with VALTOCO no more frequently than every five days and no more than five times per month.

VALTOCO is not recommended for chronic, daily use as an anticonvulsant. Chronic daily use of diazepam may increase the frequency and/or severity of tonic clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures.

Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

{ "type": "p", "children": [], "text": "Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage." }

In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

{ "type": "p", "children": [], "text": "In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information." }

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

{ "type": "p", "children": [], "text": "Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations." }

Diazepam, the active ingredient of VALTOCO nasal spray, is a benzodiazepine anticonvulsant with the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; its molecular formula is C16H13ClN2O and its molecular weight is 284.7 g/mol. The structural formula is as follows:

{ "type": "p", "children": [], "text": "Diazepam, the active ingredient of VALTOCO nasal spray, is a benzodiazepine anticonvulsant with the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; its molecular formula is C16H13ClN2O and its molecular weight is 284.7 g/mol. The structural formula is as follows:" }

The inactive ingredients in VALTOCO nasal spray include benzyl alcohol (10.5 mg per 0.1 mL), dehydrated alcohol, n-dodecyl beta-D-maltoside, and vitamin E. VALTOCO nasal spray is a clear pale amber liquid.

{ "type": "p", "children": [], "text": "The inactive ingredients in VALTOCO nasal spray include benzyl alcohol (10.5 mg per 0.1 mL), dehydrated alcohol, n-dodecyl beta-D-maltoside, and vitamin E. VALTOCO nasal spray is a clear pale amber liquid." }

The exact mechanism of action for diazepam is not fully understood, but it is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABAA receptor.

The effects of diazepam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Pharmacokinetic information for VALTOCO following nasal administration was obtained from studies conducted in healthy adult subjects, as well as adult and pediatric patients with epilepsy 2 years of age and older.

Absorption

In a pharmacokinetic study in healthy adult subjects, the highest plasma diazepam concentrations after nasal administration of VALTOCO was reached in 1.5 hours. The estimated volume of distribution of diazepam at steady-state is 0.8 to 1.0 L/kg. The absolute bioavailability of VALTOCO relative to intravenous diazepam was 97%. The mean elimination half-life of diazepam following administration of a 10 mg dose of VALTOCO was found to be about 49.2 hours. In another pharmacokinetic study in healthy adult subjects, diazepam plasma exposures (Cmax and AUC) increased approximately proportional to dose from 5 mg to 20 mg.

In a relative bioavailability study in healthy adult subjects, diazepam exposure (Cmax and AUCs) was evaluated following administration of 15 and 20 mg of VALTOCO nasal spray and diazepam rectal gel. The diazepam PK parameters were 2 to 4-fold less variable for VALTOCO and within the range of those seen with diazepam rectal gel.

In a pharmacokinetic study in patients with epilepsy, pharmacokinetic parameters were similar between seizure versus non-seizure states.

Distribution

Both diazepam and its major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).

Metabolism and Elimination

In vitro studies using human liver preparations suggest that CYP2C19 and CYP3A4 are the principal isozymes involved in the initial oxidative metabolism of diazepam. It has been reported in the literature that diazepam is extensively metabolized to one major active metabolite, desmethyldiazepam, and two minor active metabolites, 3- hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam), in plasma. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. The marked inter-individual variability in the clearance of diazepam reported in the literature is probably attributable to variability of CYP2C19 (which is known to exhibit genetic polymorphism; about 3-5% of Caucasians have little or no activity and are "poor metabolizers") and CYP3A4. No inhibition was demonstrated in the presence of inhibitors selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that these enzymes are not significantly involved in metabolism of diazepam.

Specific Populations

Geriatric Patients

A study of single dose IV administration of diazepam (0.1 mg/kg) indicates that the elimination half-life of diazepam increases linearly with age, ranging from about 15 hours at 18 years (healthy young adults) to about 100 hours at 95 years (healthy elderly) with a corresponding decrease in clearance of free diazepam [see Use in Specific Populations (8.5)].

Pediatric Patients

Literature review indicates that following IV administration (0.33 mg/kg), diazepam has a half-life in pediatric patients 6 to 12 years of age of approximately 15-21 hours. Based on simulation studies, in pediatric patients 2 to 5 years of age, median maximum plasma concentration (Cmax) and median area under the plasma concentration curve (AUC0-t) of diazepam following a single administration of VALTOCO are approximately 2-times greater than in adults. In pediatric patients 6 to 11 years of age, median Cmax and median AUC0-t of diazepam following a single administration of VALTOCO are approximately 1.4-times greater than in adults.

Patients with Renal Impairment

The pharmacokinetics of diazepam have not been studied in subjects with renal impairment.

Patients with Hepatic Impairment

No pharmacokinetic studies were conducted with VALTOCO in subjects with hepatic impairment. Literature review indicates that following administration of 0.1 to 0.15 mg/kg of diazepam intravenously, the half-life of diazepam was prolonged by two to five-fold in subjects with alcoholic cirrhosis (n=24) compared to age-matched control subjects (n=37) with a corresponding decrease in clearance by half. However, the exact degree of hepatic impairment in these subjects was not characterized in this literature.

Effect of Gender, Race, and Cigarette Smoking

No targeted pharmacokinetic studies have been conducted to evaluate the effect of gender, race, and cigarette smoking on the pharmacokinetics of diazepam. However, covariate analysis of a population of treated patients following administration of diazepam rectal gel, indicated that neither gender nor cigarette smoking had any effect on the pharmacokinetics of diazepam.

Carcinogenesis

The carcinogenic potential of diazepam delivered by the intranasal route of administration has not been evaluated. In studies in which mice and rats were administered diazepam orally in the diet at a dose of 75 mg/kg/day (approximately 10 and 20 times, respectively, the maximum recommended human dose [MRHD=0.6 mg/kg/day] on a mg/m2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species.

Mutagenesis

The data currently available are inadequate to determine the mutagenic potential of diazepam.

Impairment of Fertility

Reproduction studies with orally administered diazepam in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 27 times the MRHD on a mg/m2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 22 times the MRHD on a mg/m2 basis).

The efficacy of VALTOCO is based on the relative bioavailability of VALTOCO nasal spray compared to diazepam rectal gel in healthy adults [see Clinical Pharmacology (12.3)].

{ "type": "p", "children": [], "text": "The efficacy of VALTOCO is based on the relative bioavailability of VALTOCO nasal spray compared to diazepam rectal gel in healthy adults [see Clinical Pharmacology (12.3)].\n" }

The effectiveness of diazepam rectal gel has been established in two adequate and well-controlled clinical studies in children and adults exhibiting seizure patterns.

{ "type": "p", "children": [], "text": "The effectiveness of diazepam rectal gel has been established in two adequate and well-controlled clinical studies in children and adults exhibiting seizure patterns." }

A randomized, double-blind study compared sequential doses of diazepam rectal gel and placebo in 91 patients (47 children, 44 adults) exhibiting the appropriate seizure profile. The first dose was given at the onset of an identified episode. Children were dosed again four hours after the first dose and were observed for a total of 12 hours. Adults were dosed at four and 12 hours after the first dose and were observed for a total of 24 hours. Primary outcomes for this study were seizure frequency during the period of observation and a global assessment that took into account the severity and nature of the seizures as well as their frequency.

{ "type": "p", "children": [], "text": "A randomized, double-blind study compared sequential doses of diazepam rectal gel and placebo in 91 patients (47 children, 44 adults) exhibiting the appropriate seizure profile. The first dose was given at the onset of an identified episode. Children were dosed again four hours after the first dose and were observed for a total of 12 hours. Adults were dosed at four and 12 hours after the first dose and were observed for a total of 24 hours. Primary outcomes for this study were seizure frequency during the period of observation and a global assessment that took into account the severity and nature of the seizures as well as their frequency." }

The median seizure frequency for the diazepam rectal gel treated group was zero seizures per hour, compared to a median seizure frequency of 0.3 seizures per hour for the placebo group, a difference that was statistically significant (p < 0.0001). All three categories of the global assessment (seizure frequency, seizure severity, and "overall") were also found to be statistically significant in favor of diazepam rectal gel (p < 0.0001). The following histogram displays the results for the "overall" category of the global assessment.

{ "type": "p", "children": [], "text": "The median seizure frequency for the diazepam rectal gel treated group was zero seizures per hour, compared to a median seizure frequency of 0.3 seizures per hour for the placebo group, a difference that was statistically significant (p < 0.0001). All three categories of the global assessment (seizure frequency, seizure severity, and \"overall\") were also found to be statistically significant in favor of diazepam rectal gel (p < 0.0001). The following histogram displays the results for the \"overall\" category of the global assessment." }

Figure 1: Caregiver Overall Global Assessment of the Efficacy of Diazepam Rectal Gel

{ "type": "p", "children": [], "text": "\nFigure 1: Caregiver Overall Global Assessment of the Efficacy of Diazepam Rectal Gel\n" }

Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0002) as shown in the following graph.

{ "type": "p", "children": [], "text": "Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0002) as shown in the following graph." }

Figure 2: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - First Study

{ "type": "p", "children": [], "text": "\nFigure 2: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - First Study\n" }

In addition, 62% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 20% of placebo patients.

{ "type": "p", "children": [], "text": "In addition, 62% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 20% of placebo patients." }

Analysis of response by gender and age revealed no substantial differences between treatment in either of these subgroups. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians.

{ "type": "p", "children": [], "text": "Analysis of response by gender and age revealed no substantial differences between treatment in either of these subgroups. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians." }

A second double-blind study compared single doses of diazepam rectal gel and placebo in 114 patients (53 children, 61 adults). The dose was given at the onset of the identified episode and patients were observed for a total of 12 hours. The primary outcome in this study was seizure frequency. The median seizure frequency for the diazepam rectal gel-treated group was zero seizures per 12 hours, compared to a median seizure frequency of 2.0 seizures per 12 hours for the placebo group, a difference that was statistically significant (p < 0.03). Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0072) as shown in Figure 3.

{ "type": "p", "children": [], "text": "A second double-blind study compared single doses of diazepam rectal gel and placebo in 114 patients (53 children, 61 adults). The dose was given at the onset of the identified episode and patients were observed for a total of 12 hours. The primary outcome in this study was seizure frequency. The median seizure frequency for the diazepam rectal gel-treated group was zero seizures per 12 hours, compared to a median seizure frequency of 2.0 seizures per 12 hours for the placebo group, a difference that was statistically significant (p < 0.03). Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0072) as shown in Figure 3.\n" }

Figure 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - Second Study

{ "type": "p", "children": [], "text": "\nFigure 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - Second Study\n" }

In addition, 55% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 34% of patients receiving placebo. Overall, caregivers judged diazepam rectal gel to be more effective than placebo (p = 0.018), based on a 10-centimeter visual analog scale. In addition, investigators also evaluated the effectiveness of diazepam rectal gel and judged diazepam rectal gel to be more effective than placebo (p < 0.001).

{ "type": "p", "children": [], "text": "In addition, 55% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 34% of patients receiving placebo. Overall, caregivers judged diazepam rectal gel to be more effective than placebo (p = 0.018), based on a 10-centimeter visual analog scale. In addition, investigators also evaluated the effectiveness of diazepam rectal gel and judged diazepam rectal gel to be more effective than placebo (p < 0.001)." }

An analysis of response by gender revealed a statistically significant difference between treatments in females but not in males in this study, and the difference between the 2 genders in response to the treatments reached borderline statistical significance. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians.

{ "type": "p", "children": [], "text": "An analysis of response by gender revealed a statistically significant difference between treatments in females but not in males in this study, and the difference between the 2 genders in response to the treatments reached borderline statistical significance. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians." }

VALTOCO is available in 5 mg, 7.5 mg, and 10 mg strengths. VALTOCO is supplied and packaged in doses of 5 mg, 10 mg, 15 mg, or 20 mg (see Table 5).

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 5: Available Packaging Configurations</span> </caption> <col align="center" valign="middle" width="15%"/> <col align="left" valign="middle" width="65%"/> <col align="center" valign="middle" width="20%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Description</th><th align="center" class="Rrule">Contents</th><th align="center" class="Rrule">NDC</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="3"><span class="Bold">Each Carton Contains 2 Doses</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">5 mg carton</td><td align="left" class="Rrule">2 individual blister packs, each containing one 5 mg nasal spray device</td><td align="center" class="Rrule">72252-505-02</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">10 mg carton</td><td align="left" class="Rrule">2 individual blister packs, each containing one 10 mg nasal spray device</td><td align="center" class="Rrule">72252-510-02</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">15 mg carton</td><td align="left" class="Rrule">2 individual blister packs, each containing two 7.5 mg nasal spray devices</td><td align="center" class="Rrule">72252-515-04</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">20 mg carton</td><td align="left" class="Rrule">2 individual blister packs, each containing two 10 mg nasal spray devices</td><td align="center" class="Rrule">72252-520-04</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="3"><span class="Bold">Each Carton Contains 5 Doses</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">5 mg carton</td><td align="left" class="Rrule">5 individual blister packs, each containing one 5 mg nasal spray device</td><td align="center" class="Rrule">72252-505-05</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">10 mg carton</td><td align="left" class="Rrule">5 individual blister packs, each containing one 10 mg nasal spray device</td><td align="center" class="Rrule">72252-510-05</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">15 mg carton</td><td align="left" class="Rrule">5 individual blister packs, each containing two 7.5 mg nasal spray devices</td><td align="center" class="Rrule">72252-515-10</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">20 mg carton</td><td align="left" class="Rrule">5 individual blister packs, each containing two 10 mg nasal spray devices</td><td align="center" class="Rrule">72252-520-10</td> </tr> </tbody> </table></div>

Do not open individual blister packs or test nasal spray devices before use.

Each single-dose nasal spray device sprays one (1) time and cannot be re-used.

Do not use if the nasal spray unit appears damaged.

Store VALTOCO at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light.

Concomitant use with Opioids

Concomitant use of benzodiazepines, including VALTOCO, and opioids may result in profound sedation, respiratory depression, coma, and death. Do not use such drugs concomitantly unless supervised by a health care provider [see Warnings and Precautions (5.1)].

Abuse, Misuse, and Addiction

Inform patients that the use of VALTOCO more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)].

Withdrawal Reactions

Inform patients that use of VALTOCO more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of VALTOCO may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].

Important Treatment Instructions

Instruct patients and caregivers on what is and is not an intermittent and stereotypic episode of increased seizure activity (i.e., seizure cluster) that is appropriate for treatment, and the timing of administration in relation to the onset of the episode.

Instruct patients and caregivers on what to observe following administration, and what would constitute an outcome requiring immediate medical attention.

Instruct patients and caregivers not to administer a second dose of VALTOCO if they are concerned by the patient's breathing, the patient requires emergency rescue treatment with assisted breathing or intubation, or there is excessive sedation [see Use in Specific Populations (8.6)].

Advise patients and caregivers on how frequently they can treat successive seizure cluster episodes over time.

Pregnancy

Advise pregnant females that the use of VALTOCO 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 newborns [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant while taking VALTOCO. The registry is collecting information about the safety of antiepileptic drugs during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Counsel patients that diazepam, the active ingredient in VALTOCO, is excreted in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients who take VALTOCO to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs [see Use in Specific Populations (8.2)].

NEURELIS, VALTOCO and the NEURELIS and VALTOCO logos are registered trademarks of Neurelis, Inc.

{ "type": "p", "children": [], "text": "NEURELIS, VALTOCO and the NEURELIS and VALTOCO logos are registered trademarks of Neurelis, Inc." }

Distributed by: Neurelis, Inc. San Diego, CA 92121 USA

{ "type": "p", "children": [], "text": "Distributed by: Neurelis, Inc. San Diego, CA 92121 USA" }

© 2025 Neurelis, Inc. All rights reserved.

{ "type": "p", "children": [], "text": "© 2025 Neurelis, Inc. All rights reserved." }

Neurelis Rev. 04/2025 US-PRC-25-00099-v1

{ "type": "p", "children": [], "text": "Neurelis Rev. 04/2025 US-PRC-25-00099-v1" }

<div class="scrollingtable"><table width="100%"> <col align="left" valign="top" width="2%"/> <col align="left" valign="top" width="26%"/> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="27%"/> <col align="left" valign="top" width="27%"/> <thead> <tr class="Botrule First Last"> <th align="center" class="Lrule Rrule" colspan="5">MEDICATION GUIDE<br/> VALTOCO<span class="Sup">®</span> (val-toe-koe)<br/> (diazepam nasal spray), CIV</th> </tr> </thead> <tfoot> <tr class="First"> <td align="left" colspan="4">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="center" colspan="1">Revised: 04/2025 US-PRC-25-00100-v1</td> </tr> <tr class="Last"> <td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td><td align="left"></td> </tr> </tfoot> <tbody> <tr class="First"> <td align="left" class="Lrule Rrule" colspan="5"> <p class="First"> <a name="Whatis"></a><span class="Bold">What is the most important information I should know about VALTOCO?</span> </p> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">VALTOCO is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death.</span> Get emergency medical help right away if any of the following happens:<ul class="Circle"> <li>shallow or slowed breathing</li> <li>breathing stops (which may lead to the heart stopping)</li> <li>excessive sleepiness (sedation)</li> </ul>Do not drive or operate heavy machinery until you know how taking VALTOCO with opioids affects you. </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Risk of abuse, misuse, and addiction.</span> There is a risk for abuse, misuse, and addiction with benzodiazepines, including VALTOCO, which can lead to overdose and serious side effects including coma and death. <ul class="Circle"> <li> <span class="Bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including diazepam (the active ingredient in VALTOCO).</span> These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <span class="Bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.</span> </li> <li>You can develop an addiction even if you use VALTOCO as prescribed by your healthcare provider.</li> <li> <span class="Bold">Use VALTOCO exactly as your healthcare provider prescribed.</span> </li> <li>Do not share your VALTOCO with other people.</li> <li>Keep VALTOCO in a safe place and away from children.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Physical dependence and withdrawal reactions</span>. Benzodiazepines, including VALTOCO, can cause physical dependence and withdrawal reactions, especially if you use VALTOCO daily. VALTOCO is not intended for daily use.<ul class="Circle"> <li> <span class="Bold">Do not suddenly stop using VALTOCO without talking to your healthcare provider.</span> Stopping VALTOCO suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <span class="Bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</span> </li> <li> <span class="Bold">Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months</span>, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.</li> <li>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. </li> <li>Do not use more VALTOCO than prescribed or use VALTOCO more often than prescribed.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">VALTOCO can make you sleepy or dizzy and can slow your thinking and motor skills.</span> <ul class="Circle"> <li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how VALTOCO affects you.</li> <li>Do not drink alcohol or take other drugs that may make you sleepy or dizzy while using VALTOCO without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, VALTOCO may make your sleepiness or dizziness worse.</li> </ul> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Like other antiepileptic medicines, VALTOCO may cause suicidal thoughts or actions in a small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you</span>:</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left" colspan="2"> <ul class="Circle"> <li>thoughts about suicide or dying</li> <li>feeling agitated or restless</li> <li>acting aggressive, being angry, or violent</li> <li>attempts to commit suicide</li> <li>panic attacks</li> <li>acting on dangerous impulses</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Circle"> <li>trouble sleeping (insomnia)</li> <li>an extreme increase in activity and talking (mania)</li> <li>new or worse anxiety</li> <li>new or worse irritability</li> <li>other unusual changes in behavior or mood</li> <li>new or worse depression</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule"></td><td align="left" class="Rrule" colspan="4"><span class="Bold">How can I watch for early symptoms of suicidal thoughts or actions?</span> <ul class="Circle"> <li>Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.</li> <li>Keep all follow-up visits with your healthcare provider as scheduled.</li> </ul>Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What is VALTOCO?</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li>VALTOCO is a prescription medicine used for short-term treatment of seizure clusters (also known as "acute repetitive seizures") that are different from a person's normal seizure pattern in people 2 years of age and older.</li> <li> <span class="Bold">VALTOCO is a federally controlled substance (C-IV) because it contains diazepam that can be abused or lead to dependence. </span> Keep VALTOCO in a safe place to prevent misuse and abuse. Selling or giving away VALTOCO may harm others and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription drugs, or street drugs.</li> <li>It is not known if VALTOCO is safe and effective in children under 2 years of age.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <p class="First"> <a name="Donot"></a><span class="Bold">Do not use VALTOCO if you:</span> </p> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li>are allergic to diazepam or any of the ingredients in VALTOCO. See the end of this Medication Guide for a complete list of ingredients in VALTOCO.</li> <li>have an eye problem called acute narrow angle glaucoma.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Before using VALTOCO, tell your healthcare provider about all of your medical conditions, including if you:</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li>have asthma, emphysema, bronchitis, chronic obstructive pulmonary disease, or other breathing problems.</li> <li>have a history of alcohol or drug abuse.</li> <li>have a history of depression, mood problems or suicidal thoughts or behaviors.</li> <li>have liver or kidney problems.</li> <li>are pregnant or plan to become pregnant.<ul class="Circle"> <li>Taking VALTOCO late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone) and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</li> <li>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with VALTOCO.</li> <li>If you become pregnant while using VALTOCO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry, go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.</li> </ul> </li> <li>are breastfeeding or plan to breastfeed. VALTOCO passes into your breast milk and may harm your baby.<ul class="Circle"> <li>Breastfeeding during treatment with VALTOCO may cause your baby to have sleepiness, feeding problems, and decreased weight gain.</li> <li>Talk to your healthcare provider about the best way to feed your baby if you use VALTOCO.</li> </ul> </li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using VALTOCO with certain other medicines can cause side effects or affect how well VALTOCO or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I use VALTOCO?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li> <span class="Bold">Read the Instructions for Use that comes with this Medication Guide for detailed information about the right way to use VALTOCO.</span> </li> <li>Use VALTOCO exactly as prescribed by your healthcare provider.</li> <li>Your healthcare provider will tell you:<ul class="Circle"> <li>what seizure clusters are</li> <li>exactly how much VALTOCO to give</li> <li>when to give VALTOCO</li> <li>how to give VALTOCO</li> <li>what to do after you give VALTOCO if the seizures do not stop or there is a change in breathing, behavior, or condition that worries you</li> </ul> </li> <li>You should carry VALTOCO with you in case you need it to control your seizure clusters.</li> <li>Family members, care providers, and other people who may have to give VALTOCO should know where you keep your VALTOCO and how to give VALTOCO before a seizure cluster happens.</li> <li>VALTOCO is given in the nose (nasal) only.</li> <li> <span class="Bold">Do not</span> test or prime the nasal spray before use.</li> <li>Each VALTOCO only sprays 1 time and cannot be reused.</li> <li>Each dose of VALTOCO is provided in an individual pack. Use all of the medicine in 1 pack for a complete dose.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What should I do after I give VALTOCO?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li>Stay with the person after you give VALTOCO and watch them closely.</li> <li>Make a note of the time VALTOCO was given.</li> <li>Call for emergency help if any of the following happen:<ul class="Circle"> <li>seizure cluster behavior is different than other seizure clusters the person has had.</li> <li>you are alarmed by how often the seizures happen, by how severe the seizure is, by how long the seizure lasts, or by the color or breathing of the person.</li> </ul> </li> <li>Throw away (discard) the used VALTOCO.</li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5">If needed, a second dose may be given at least 4 hours after the first dose, using a new pack of VALTOCO. Do not give more than 2 doses of VALTOCO to treat a seizure cluster.<br/> A second dose should <span class="Bold">not</span> be given if there is concern about the person's breathing, they need help with their breathing, or have extreme drowsiness.</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">Do not use VALTOCO for more than 1 seizure cluster episode every 5 days. Do not use VALTOCO for more than 5 seizure cluster episodes in 1 month.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What should I avoid while using VALTOCO?</span> <br/>See <span class="Bold">"<a href="#Whatis">What is the most important information I should know about VALTOCO?</a>"</span> <br/> <span class="Bold">What are the possible side effects of VALTOCO?</span> <br/> <span class="Bold">VALTOCO may cause serious side effects, including:</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li>See <span class="Bold">"<a href="#Whatis">What is the most important information I should know about VALTOCO?</a>"</span> </li> <li> <span class="Bold">Increase in eye pressure in people with open-angle glaucoma.</span> See <span class="Bold">"<a href="#Donot">Do not use VALTOCO if you:</a>"</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">The most common side effects of VALTOCO include:</span></td> </tr> <tr> <td align="left" class="Lrule"></td><td align="left"> <ul class="Disc"> <li>feeling sleepy or drowsy</li> </ul> </td><td align="left"> <ul class="Disc"> <li>headache</li> </ul> </td><td align="left" class="Rrule" colspan="2"> <ul class="Disc"> <li>nose discomfort</li> </ul> </td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">These are not all of the possible side effects of VALTOCO. Call your doctor for medical advice about side effects.<br/>You may report side effects to FDA at 1-800-FDA-1088.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">How should I store VALTOCO?</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"> <ul class="Disc"> <li>Store VALTOCO at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Do not freeze VALTOCO.</li> <li>Keep VALTOCO in its blister pack until ready to use. Protect it from light.</li> <li> <span class="Bold">Keep VALTOCO and all medicines out of the reach of children.</span> </li> </ul> </td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">General information about the safe and effective use of VALTOCO.</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5">Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VALTOCO for a condition for which it was not prescribed. Do not give VALTOCO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VALTOCO that is written for health professionals.</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">What are the ingredients in VALTOCO?</span></td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Active ingredient:</span> diazepam</td> </tr> <tr> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Inactive ingredients:</span> benzyl alcohol, dehydrated alcohol, n-dodecyl beta-D-maltoside, and vitamin E.</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule" colspan="5">Distributed by Neurelis, Inc., San Diego, CA 92121 USA. NEURELIS and VALTOCO and the NEURELIS and VALTOCO logos are registered trademarks of Neurelis, Inc.<br/> For more information, go to www.valtoco.com or call 1-866-696-3873.</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"2%\"/>\n<col align=\"left\" valign=\"top\" width=\"26%\"/>\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"left\" valign=\"top\" width=\"27%\"/>\n<col align=\"left\" valign=\"top\" width=\"27%\"/>\n<thead>\n<tr class=\"Botrule First Last\">\n<th align=\"center\" class=\"Lrule Rrule\" colspan=\"5\">MEDICATION GUIDE<br/> VALTOCO<span class=\"Sup\">®</span> (val-toe-koe)<br/> (diazepam nasal spray), CIV</th>\n</tr>\n</thead>\n<tfoot>\n<tr class=\"First\">\n<td align=\"left\" colspan=\"4\">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align=\"center\" colspan=\"1\">Revised: 04/2025 US-PRC-25-00100-v1</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td><td align=\"left\"></td>\n</tr>\n</tfoot>\n<tbody>\n<tr class=\"First\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<p class=\"First\">\n<a name=\"Whatis\"></a><span class=\"Bold\">What is the most important information I should know about VALTOCO?</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">VALTOCO is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma, and death.</span> Get emergency medical help right away if any of the following happens:<ul class=\"Circle\">\n<li>shallow or slowed breathing</li>\n<li>breathing stops (which may lead to the heart stopping)</li>\n<li>excessive sleepiness (sedation)</li>\n</ul>Do not drive or operate heavy machinery until you know how taking VALTOCO with opioids affects you. \t\t\t\t\t\t\t\t\t\t\t</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Risk of abuse, misuse, and addiction.</span> There is a risk for abuse, misuse, and addiction with benzodiazepines, including VALTOCO, which can lead to overdose and serious side effects including coma and death. <ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including diazepam (the active ingredient in VALTOCO).</span> These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <span class=\"Bold\">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.</span>\n</li>\n<li>You can develop an addiction even if you use VALTOCO as prescribed by your healthcare provider.</li>\n<li>\n<span class=\"Bold\">Use VALTOCO exactly as your healthcare provider prescribed.</span>\n</li>\n<li>Do not share your VALTOCO with other people.</li>\n<li>Keep VALTOCO in a safe place and away from children.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Physical dependence and withdrawal reactions</span>. Benzodiazepines, including VALTOCO, can cause physical dependence and withdrawal reactions, especially if you use VALTOCO daily. VALTOCO is not intended for daily use.<ul class=\"Circle\">\n<li>\n<span class=\"Bold\">Do not suddenly stop using VALTOCO without talking to your healthcare provider.</span> Stopping VALTOCO suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <span class=\"Bold\">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</span>\n</li>\n<li>\n<span class=\"Bold\">Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months</span>, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.</li>\n<li>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. </li>\n<li>Do not use more VALTOCO than prescribed or use VALTOCO more often than prescribed.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">VALTOCO can make you sleepy or dizzy and can slow your thinking and motor skills.</span>\n<ul class=\"Circle\">\n<li>Do not drive, operate heavy machinery, or do other dangerous activities until you know how VALTOCO affects you.</li>\n<li>Do not drink alcohol or take other drugs that may make you sleepy or dizzy while using VALTOCO without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, VALTOCO may make your sleepiness or dizziness worse.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Like other antiepileptic medicines, VALTOCO may cause suicidal thoughts or actions in a small number of people, about 1 in 500. Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you</span>:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>thoughts about suicide or dying</li>\n<li>feeling agitated or restless</li>\n<li>acting aggressive, being angry, or violent</li>\n<li>attempts to commit suicide</li>\n<li>panic attacks</li>\n<li>acting on dangerous impulses</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>trouble sleeping (insomnia)</li>\n<li>an extreme increase in activity and talking (mania)</li>\n<li>new or worse anxiety</li>\n<li>new or worse irritability</li>\n<li>other unusual changes in behavior or mood</li>\n<li>new or worse depression</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\" class=\"Rrule\" colspan=\"4\"><span class=\"Bold\">How can I watch for early symptoms of suicidal thoughts or actions?</span>\n<ul class=\"Circle\">\n<li>Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.</li>\n<li>Keep all follow-up visits with your healthcare provider as scheduled.</li>\n</ul>Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes. \t\t\t\t\t\t\t\t\t</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What is VALTOCO?</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>VALTOCO is a prescription medicine used for short-term treatment of seizure clusters (also known as \"acute repetitive seizures\") that are different from a person's normal seizure pattern in people 2 years of age and older.</li>\n<li>\n<span class=\"Bold\">VALTOCO is a federally controlled substance (C-IV) because it contains diazepam that can be abused or lead to dependence. </span> Keep VALTOCO in a safe place to prevent misuse and abuse. Selling or giving away VALTOCO may harm others and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription drugs, or street drugs.</li>\n<li>It is not known if VALTOCO is safe and effective in children under 2 years of age.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<p class=\"First\">\n<a name=\"Donot\"></a><span class=\"Bold\">Do not use VALTOCO if you:</span>\n</p>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>are allergic to diazepam or any of the ingredients in VALTOCO. See the end of this Medication Guide for a complete list of ingredients in VALTOCO.</li>\n<li>have an eye problem called acute narrow angle glaucoma.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Before using VALTOCO, tell your healthcare provider about all of your medical conditions, including if you:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>have asthma, emphysema, bronchitis, chronic obstructive pulmonary disease, or other breathing problems.</li>\n<li>have a history of alcohol or drug abuse.</li>\n<li>have a history of depression, mood problems or suicidal thoughts or behaviors.</li>\n<li>have liver or kidney problems.</li>\n<li>are pregnant or plan to become pregnant.<ul class=\"Circle\">\n<li>Taking VALTOCO late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone) and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</li>\n<li>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with VALTOCO.</li>\n<li>If you become pregnant while using VALTOCO, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. You can register by calling 1-888-233-2334. For more information about the registry, go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.</li>\n</ul>\n</li>\n<li>are breastfeeding or plan to breastfeed. VALTOCO passes into your breast milk and may harm your baby.<ul class=\"Circle\">\n<li>Breastfeeding during treatment with VALTOCO may cause your baby to have sleepiness, feeding problems, and decreased weight gain.</li>\n<li>Talk to your healthcare provider about the best way to feed your baby if you use VALTOCO.</li>\n</ul>\n</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Tell your healthcare provider about all the medicines you take</span>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using VALTOCO with certain other medicines can cause side effects or affect how well VALTOCO or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I use VALTOCO?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Read the Instructions for Use that comes with this Medication Guide for detailed information about the right way to use VALTOCO.</span>\n</li>\n<li>Use VALTOCO exactly as prescribed by your healthcare provider.</li>\n<li>Your healthcare provider will tell you:<ul class=\"Circle\">\n<li>what seizure clusters are</li>\n<li>exactly how much VALTOCO to give</li>\n<li>when to give VALTOCO</li>\n<li>how to give VALTOCO</li>\n<li>what to do after you give VALTOCO if the seizures do not stop or there is a change in breathing, behavior, or condition that worries you</li>\n</ul>\n</li>\n<li>You should carry VALTOCO with you in case you need it to control your seizure clusters.</li>\n<li>Family members, care providers, and other people who may have to give VALTOCO should know where you keep your VALTOCO and how to give VALTOCO before a seizure cluster happens.</li>\n<li>VALTOCO is given in the nose (nasal) only.</li>\n<li>\n<span class=\"Bold\">Do not</span> test or prime the nasal spray before use.</li>\n<li>Each VALTOCO only sprays 1 time and cannot be reused.</li>\n<li>Each dose of VALTOCO is provided in an individual pack. Use all of the medicine in 1 pack for a complete dose.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What should I do after I give VALTOCO?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>Stay with the person after you give VALTOCO and watch them closely.</li>\n<li>Make a note of the time VALTOCO was given.</li>\n<li>Call for emergency help if any of the following happen:<ul class=\"Circle\">\n<li>seizure cluster behavior is different than other seizure clusters the person has had.</li>\n<li>you are alarmed by how often the seizures happen, by how severe the seizure is, by how long the seizure lasts, or by the color or breathing of the person.</li>\n</ul>\n</li>\n<li>Throw away (discard) the used VALTOCO.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">If needed, a second dose may be given at least 4 hours after the first dose, using a new pack of VALTOCO. Do not give more than 2 doses of VALTOCO to treat a seizure cluster.<br/> A second dose should <span class=\"Bold\">not</span> be given if there is concern about the person's breathing, they need help with their breathing, or have extreme drowsiness.</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Do not use VALTOCO for more than 1 seizure cluster episode every 5 days. Do not use VALTOCO for more than 5 seizure cluster episodes in 1 month.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What should I avoid while using VALTOCO?</span>\n<br/>See <span class=\"Bold\">\"<a href=\"#Whatis\">What is the most important information I should know about VALTOCO?</a>\"</span>\n<br/>\n<span class=\"Bold\">What are the possible side effects of VALTOCO?</span>\n<br/>\n<span class=\"Bold\">VALTOCO may cause serious side effects, including:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>See <span class=\"Bold\">\"<a href=\"#Whatis\">What is the most important information I should know about VALTOCO?</a>\"</span>\n</li>\n<li>\n<span class=\"Bold\">Increase in eye pressure in people with open-angle glaucoma.</span> See <span class=\"Bold\">\"<a href=\"#Donot\">Do not use VALTOCO if you:</a>\"</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">The most common side effects of VALTOCO include:</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule\"></td><td align=\"left\">\n<ul class=\"Disc\">\n<li>feeling sleepy or drowsy</li>\n</ul>\n</td><td align=\"left\">\n<ul class=\"Disc\">\n<li>headache</li>\n</ul>\n</td><td align=\"left\" class=\"Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>nose discomfort</li>\n</ul>\n</td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">These are not all of the possible side effects of VALTOCO. Call your doctor for medical advice about side effects.<br/>You may report side effects to FDA at 1-800-FDA-1088.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">How should I store VALTOCO?</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">\n<ul class=\"Disc\">\n<li>Store VALTOCO at room temperature between 68°F to 77°F (20°C to 25°C).</li>\n<li>Do not freeze VALTOCO.</li>\n<li>Keep VALTOCO in its blister pack until ready to use. Protect it from light.</li>\n<li>\n<span class=\"Bold\">Keep VALTOCO and all medicines out of the reach of children.</span>\n</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">General information about the safe and effective use of VALTOCO.</span></td>\n</tr>\n<tr class=\"Botrule\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VALTOCO for a condition for which it was not prescribed. Do not give VALTOCO to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VALTOCO that is written for health professionals.</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">What are the ingredients in VALTOCO?</span></td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Active ingredient:</span> diazepam</td>\n</tr>\n<tr>\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\"><span class=\"Bold\">Inactive ingredients:</span> benzyl alcohol, dehydrated alcohol, n-dodecyl beta-D-maltoside, and vitamin E.</td>\n</tr>\n<tr class=\"Last\">\n<td align=\"left\" class=\"Lrule Rrule\" colspan=\"5\">Distributed by Neurelis, Inc., San Diego, CA 92121 USA. NEURELIS and VALTOCO and the NEURELIS and VALTOCO logos are registered trademarks of Neurelis, Inc.<br/> For more information, go to www.valtoco.com or call 1-866-696-3873.</td>\n</tr>\n</tbody>\n</table></div>" }

For 5 mg and 10 mg Doses

{ "type": "p", "children": [], "text": "\nFor 5 mg and 10 mg Doses\n" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

You, your family members, caregivers, and others who may need to give VALTOCO should read these Instructions for Use before using it. Talk to your healthcare provider if you, your caregiver, or others who may need to give VALTOCO have any questions about the use of VALTOCO.

{ "type": "p", "children": [], "text": "You, your family members, caregivers, and others who may need to give VALTOCO should read these Instructions for Use before using it. Talk to your healthcare provider if you, your caregiver, or others who may need to give VALTOCO have any questions about the use of VALTOCO." }

Important: For Nasal Use Only.

{ "type": "p", "children": [], "text": "\nImportant: For Nasal Use Only.\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="60%"/> <col align="left" valign="top" width="5%"/> <col align="left" valign="top" width="35%"/> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Do not</span> test or prime the nasal spray device. Each device sprays one time only.<br/> <span class="Bold">Do not</span> use past the expiration date printed on box and blister pack.<br/> <span class="Bold">Do not</span> open blister pack until ready to use.</td><td align="left"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=valtoco-05.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Each blister pack contains<br/> 1 nasal spray device.<br/> 1 dose = 1 nasal spray device.</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"60%\"/>\n<col align=\"left\" valign=\"top\" width=\"5%\"/>\n<col align=\"left\" valign=\"top\" width=\"35%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"><span class=\"Bold\">Do not</span> test or prime the nasal spray device. Each device sprays one time only.<br/>\n<span class=\"Bold\">Do not</span> use past the expiration date printed on box and blister pack.<br/>\n<span class=\"Bold\">Do not</span> open blister pack until ready to use.</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=valtoco-05.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Each blister pack contains<br/> 1 nasal spray device.<br/> 1 dose = 1 nasal spray device.</span></td>\n</tr>\n</tbody>\n</table></div>" }

To give VALTOCO nasal spray:

{ "type": "p", "children": [], "text": "\nTo give VALTOCO nasal spray:\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="7%"/> <col align="left" valign="top" width="73%"/> <tbody class="Headless"> <tr> <td align="left"> <p class="First"> <img alt="Step 1" src="/dailymed/image.cfm?name=valtoco-06.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 1: </span></td><td align="left"><span class="Bold">Open the blister pack</span> by peeling back the corner tab with the arrow.<br/> <span class="Bold">Remove the nasal spray device</span> from the blister pack.</td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Step 2" src="/dailymed/image.cfm?name=valtoco-07.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 2: </span></td><td align="left"><span class="Bold">Hold the nasal spray device</span> with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.<br/> <span class="Bold">Do not press the plunger yet.</span> If you press the plunger now, you will lose the medicine.</td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Step 3" src="/dailymed/image.cfm?name=valtoco-08.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 3: </span></td><td align="left"><span class="Bold">Insert the tip of the nozzle into 1 nostril</span> until your fingers, on either side of the nozzle, are against the bottom of the nose.</td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Step 4" src="/dailymed/image.cfm?name=valtoco-09.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 4: </span></td><td align="left"><span class="Bold">Press the bottom of the plunger firmly</span> with your thumb to give VALTOCO.<br/> The person does not need to breathe deeply when VALTOCO is given.<br/> <span class="Bold">Remove the nasal spray device from the nose after giving VALTOCO.</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"left\" valign=\"top\" width=\"7%\"/>\n<col align=\"left\" valign=\"top\" width=\"73%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 1\" src=\"/dailymed/image.cfm?name=valtoco-06.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 1: </span></td><td align=\"left\"><span class=\"Bold\">Open the blister pack</span> by peeling back the corner tab with the arrow.<br/>\n<span class=\"Bold\">Remove the nasal spray device</span> from the blister pack.</td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 2\" src=\"/dailymed/image.cfm?name=valtoco-07.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 2: </span></td><td align=\"left\"><span class=\"Bold\">Hold the nasal spray device</span> with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.<br/>\n<span class=\"Bold\">Do not press the plunger yet.</span> If you press the plunger now, you will lose the medicine.</td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 3\" src=\"/dailymed/image.cfm?name=valtoco-08.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 3: </span></td><td align=\"left\"><span class=\"Bold\">Insert the tip of the nozzle into 1 nostril</span> until your fingers, on either side of the nozzle, are against the bottom of the nose.</td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 4\" src=\"/dailymed/image.cfm?name=valtoco-09.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 4: </span></td><td align=\"left\"><span class=\"Bold\">Press the bottom of the plunger firmly</span> with your thumb to give VALTOCO.<br/> The person does not need to breathe deeply when VALTOCO is given.<br/>\n<span class=\"Bold\">Remove the nasal spray device from the nose after giving VALTOCO.</span></td>\n</tr>\n</tbody>\n</table></div>" }

After giving VALTOCO nasal spray:

{ "type": "p", "children": [], "text": "\nAfter giving VALTOCO nasal spray:\n" }

Throw away (discard) the nasal spray device and the blister pack after use.

{ "type": "p", "children": [], "text": "Throw away (discard) the nasal spray device and the blister pack after use." }

Call for emergency help if any of the following happen:

{ "type": "p", "children": [], "text": "\nCall for emergency help if any of the following happen:\n" }

{ "type": "ul", "children": [ "Seizure behavior in the person is different from that of other episodes.", "You are alarmed by how often the seizures happen, by how severe the seizure is, by how long the seizure lasts, or by the color or breathing of the person." ], "text": "" }

Make a note of the time VALTOCO was given and continue to watch the person closely.

{ "type": "p", "children": [], "text": "\nMake a note of the time VALTOCO was given and continue to watch the person closely." }

Time of first VALTOCO dose:______________ Time of second VALTOCO dose (if given): ______________________

{ "type": "p", "children": [], "text": "\nTime of first VALTOCO dose:______________ Time of second VALTOCO dose (if given): ______________________ \t\n" }

The healthcare provider may prescribe another dose of VALTOCO to be given at least 4 hours after the first dose. If a second dose is needed, repeat Steps 1 through 4 with a new blister pack of VALTOCO.

{ "type": "p", "children": [], "text": "\nThe healthcare provider may prescribe another dose of VALTOCO to be given at least 4 hours after the first dose. If a second dose is needed, repeat Steps 1 through 4 with a new blister pack of VALTOCO." }

For more information about VALTOCO, visit www.valtoco.com or call 1-866-696-3873. Report side effects of prescription drugs to the FDA by visiting www.fda.gov/medwatch or by calling 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "For more information about VALTOCO, visit www.valtoco.com or call 1-866-696-3873. Report side effects of prescription drugs to the FDA by visiting www.fda.gov/medwatch or by calling 1-800-FDA-1088." }

These Instructions for Use have been approved by the U.S. Food and Drug Administration. Issued: 02/2022

{ "type": "p", "children": [], "text": "These Instructions for Use have been approved by the U.S. Food and Drug Administration. Issued: 02/2022" }

© Neurelis, Inc. 2022. NEURELIS, VALTOCO, and the NEURELIS and VALTOCO logos are trademarks or registered trademarks of Neurelis, Inc. US-PRC-22-00029 02/2022

{ "type": "p", "children": [], "text": "© Neurelis, Inc. 2022. NEURELIS, VALTOCO, and the NEURELIS and VALTOCO logos are trademarks or registered trademarks of Neurelis, Inc. US-PRC-22-00029 02/2022" }

For 15 mg and 20 mg Doses

{ "type": "p", "children": [], "text": "For 15 mg and 20 mg Doses" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

You, your family members, caregivers, and others who may need to give VALTOCO should read these Instructions for Use before using it. Talk to your healthcare provider if you, your caregiver, or others who may need to give VALTOCO have any questions about the use of VALTOCO.

{ "type": "p", "children": [], "text": "You, your family members, caregivers, and others who may need to give VALTOCO should read these Instructions for Use before using it. Talk to your healthcare provider if you, your caregiver, or others who may need to give VALTOCO have any questions about the use of VALTOCO." }

Important: For Nasal Use Only.

{ "type": "p", "children": [], "text": "\nImportant: For Nasal Use Only.\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="60%"/> <col align="left" valign="top" width="5%"/> <col align="left" valign="top" width="35%"/> <tbody class="Headless"> <tr> <td align="left"><span class="Bold">Do not</span> test or prime the nasal spray devices. Each device sprays one time only.<br/> <span class="Bold">Do not</span> use past the expiration date printed on box and blister pack.<br/> <span class="Bold">Do not</span> open blister pack until ready to use.</td><td align="left"> <p class="First"> <img alt="Image" src="/dailymed/image.cfm?name=valtoco-10.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Each blister pack contains<br/> 2 nasal spray devices.<br/> 1 dose = 2 nasal spray devices.</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"60%\"/>\n<col align=\"left\" valign=\"top\" width=\"5%\"/>\n<col align=\"left\" valign=\"top\" width=\"35%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\"><span class=\"Bold\">Do not</span> test or prime the nasal spray devices. Each device sprays one time only.<br/>\n<span class=\"Bold\">Do not</span> use past the expiration date printed on box and blister pack.<br/>\n<span class=\"Bold\">Do not</span> open blister pack until ready to use.</td><td align=\"left\">\n<p class=\"First\">\n<img alt=\"Image\" src=\"/dailymed/image.cfm?name=valtoco-10.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Each blister pack contains<br/> 2 nasal spray devices.<br/> 1 dose = 2 nasal spray devices.</span></td>\n</tr>\n</tbody>\n</table></div>" }

To give VALTOCO nasal spray:

{ "type": "p", "children": [], "text": "\nTo give VALTOCO nasal spray:\n" }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="left" valign="top" width="20%"/> <col align="left" valign="top" width="7%"/> <col align="left" valign="top" width="73%"/> <tbody class="Headless"> <tr> <td align="left"> <p class="First"> <img alt="Step 1" src="/dailymed/image.cfm?name=valtoco-11.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 1: </span></td><td align="left"><span class="Bold">Open the blister pack</span> by peeling back the corner tab with the arrow.<br/> <span class="Bold">Remove the first nasal spray device</span> from the blister pack.</td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Step 2" src="/dailymed/image.cfm?name=valtoco-12.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 2: </span></td><td align="left"><span class="Bold">Hold the nasal spray device</span> with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.<br/> <span class="Bold">Do not press the plunger yet.</span> If you press the plunger now, you will lose the medicine.</td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Step 3" src="/dailymed/image.cfm?name=valtoco-13.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 3: </span></td><td align="left"><span class="Bold">Insert the tip of the nozzle into 1 nostril</span> until your fingers, on either side of the nozzle, are against the bottom of the nose.</td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Step 4" src="/dailymed/image.cfm?name=valtoco-14.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 4: </span></td><td align="left"><span class="Bold">Press the bottom of the plunger firmly</span> with your thumb to give VALTOCO.<br/> The person does not need to breathe deeply when VALTOCO is given.<br/> <span class="Bold">Remove the nasal spray device from the nose after giving VALTOCO.</span></td> </tr> <tr> <td align="left"> <p class="First"> <img alt="Step 5" src="/dailymed/image.cfm?name=valtoco-15.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39"/></p> </td><td align="left"><span class="Bold">Step 5: </span></td><td align="left"><span class="Bold">You have not given the full dose of VALTOCO yet.<br/> Remove the second nasal spray device from the blister pack.<br/> Repeat Steps 2 through 4, using the second nasal spray device in the other nostril to give the full dose of VALTOCO.</span></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<col align=\"left\" valign=\"top\" width=\"20%\"/>\n<col align=\"left\" valign=\"top\" width=\"7%\"/>\n<col align=\"left\" valign=\"top\" width=\"73%\"/>\n<tbody class=\"Headless\">\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 1\" src=\"/dailymed/image.cfm?name=valtoco-11.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 1: </span></td><td align=\"left\"><span class=\"Bold\">Open the blister pack</span> by peeling back the corner tab with the arrow.<br/>\n<span class=\"Bold\">Remove the first nasal spray device</span> from the blister pack.</td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 2\" src=\"/dailymed/image.cfm?name=valtoco-12.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 2: </span></td><td align=\"left\"><span class=\"Bold\">Hold the nasal spray device</span> with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle.<br/>\n<span class=\"Bold\">Do not press the plunger yet.</span> If you press the plunger now, you will lose the medicine.</td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 3\" src=\"/dailymed/image.cfm?name=valtoco-13.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 3: </span></td><td align=\"left\"><span class=\"Bold\">Insert the tip of the nozzle into 1 nostril</span> until your fingers, on either side of the nozzle, are against the bottom of the nose.</td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 4\" src=\"/dailymed/image.cfm?name=valtoco-14.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 4: </span></td><td align=\"left\"><span class=\"Bold\">Press the bottom of the plunger firmly</span> with your thumb to give VALTOCO.<br/> The person does not need to breathe deeply when VALTOCO is given.<br/>\n<span class=\"Bold\">Remove the nasal spray device from the nose after giving VALTOCO.</span></td>\n</tr>\n<tr>\n<td align=\"left\">\n<p class=\"First\">\n<img alt=\"Step 5\" src=\"/dailymed/image.cfm?name=valtoco-15.jpg&amp;setid=1a8bcc90-68fa-474d-832c-0df01e825f39\"/></p>\n</td><td align=\"left\"><span class=\"Bold\">Step 5: </span></td><td align=\"left\"><span class=\"Bold\">You have not given the full dose of VALTOCO yet.<br/> Remove the second nasal spray device from the blister pack.<br/> Repeat Steps 2 through 4, using the second nasal spray device in the other nostril to give the full dose of VALTOCO.</span></td>\n</tr>\n</tbody>\n</table></div>" }

After giving VALTOCO nasal spray:

{ "type": "p", "children": [], "text": "\nAfter giving VALTOCO nasal spray:\n" }

Throw away (discard) both nasal spray devices and the blister pack after use.

{ "type": "p", "children": [], "text": "Throw away (discard) both nasal spray devices and the blister pack after use." }

Call for emergency help if any of the following happen:

{ "type": "p", "children": [], "text": "\nCall for emergency help if any of the following happen:\n" }

{ "type": "ul", "children": [ "Seizure behavior in the person is different from that of other episodes.", "You are alarmed by how often the seizures happen, by how severe the seizure is, by how long the seizure lasts, or by the color or breathing of the person." ], "text": "" }

Make a note of the time VALTOCO was given and continue to watch the person closely.

{ "type": "p", "children": [], "text": "\nMake a note of the time VALTOCO was given and continue to watch the person closely." }

Time of first VALTOCO dose (first dose equals 1 spray in each nostril):________________/________________ Time of second VALTOCO dose (if given, second dose equals 1 spray in each nostril):________________/________________

{ "type": "p", "children": [], "text": "\nTime of first VALTOCO dose (first dose equals 1 spray in each nostril):________________/________________ Time of second VALTOCO dose (if given, second dose equals 1 spray in each nostril):________________/________________\n" }

The healthcare provider may prescribe another dose of VALTOCO to be given at least 4 hours after the first dose. If a second dose is needed, repeat Steps 1 through 5 with a new blister pack of VALTOCO.

{ "type": "p", "children": [], "text": "\nThe healthcare provider may prescribe another dose of VALTOCO to be given at least 4 hours after the first dose. If a second dose is needed, repeat Steps 1 through 5 with a new blister pack of VALTOCO." }

For more information about VALTOCO, visit www.valtoco.com or call 1-866-696-3873. Report side effects of prescription drugs to the FDA by visiting www.fda.gov/medwatch or by calling 1-800-FDA-1088.

{ "type": "p", "children": [], "text": "For more information about VALTOCO, visit www.valtoco.com or call 1-866-696-3873. Report side effects of prescription drugs to the FDA by visiting www.fda.gov/medwatch or by calling 1-800-FDA-1088." }

These Instructions for Use have been approved by the U.S. Food and Drug Administration. Issued: 02/2022

{ "type": "p", "children": [], "text": "These Instructions for Use have been approved by the U.S. Food and Drug Administration. Issued: 02/2022" }

© Neurelis, Inc. 2022. NEURELIS, VALTOCO, and the NEURELIS and VALTOCO logos are trademarks or registered trademarks of Neurelis, Inc. US-PRC-22-00029 02/2022

{ "type": "p", "children": [], "text": "© Neurelis, Inc. 2022. NEURELIS, VALTOCO, and the NEURELIS and VALTOCO logos are trademarks or registered trademarks of Neurelis, Inc. US-PRC-22-00029 02/2022" }

NDC 72252-505-02Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-505-02Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

5 mg

{ "type": "p", "children": [], "text": "5 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

5 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY

{ "type": "p", "children": [], "text": "5 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY" }

Do NOT open blister packs ortest nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs ortest nasal sprays before use." }

This box contains 2 blister packs.Each blister pack contains 1 nasal spray device.1 device contains 1 dose (5 mg)

{ "type": "p", "children": [], "text": "This box contains 2 blister packs.Each blister pack contains 1 nasal spray device.1 device contains 1 dose (5 mg)" }

ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }

NDC 72252-505-05Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-505-05Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

5 mg

{ "type": "p", "children": [], "text": "5 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

5 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY

{ "type": "p", "children": [], "text": "5 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY" }

Do NOT open blister packs ortest nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs ortest nasal sprays before use." }

Contains 5 blister packs (5 doses).Each blister pack contains 1 nasal spray device.1 device contains 1 dose (5 mg).

{ "type": "p", "children": [], "text": "Contains 5 blister packs (5 doses).Each blister pack contains 1 nasal spray device.1 device contains 1 dose (5 mg)." }

ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }

NDC 72252-515-04Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-515-04Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

15 mg

{ "type": "p", "children": [], "text": "15 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

15 mg = 2 NASAL SPRAY DEVICESDEVICES SPRAY ONE TIME ONLY

{ "type": "p", "children": [], "text": "15 mg = 2 NASAL SPRAY DEVICESDEVICES SPRAY ONE TIME ONLY" }

Do NOT open blister packs ortest nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs ortest nasal sprays before use." }

This box contains 2 blister packs.Each blister pack contains 2 nasal spray devices.2 devices contains 1 dose (15 mg)

{ "type": "p", "children": [], "text": "This box contains 2 blister packs.Each blister pack contains 2 nasal spray devices.2 devices contains 1 dose (15 mg)" }

ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }

NDC 72252-515-10Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-515-10Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

15 mg

{ "type": "p", "children": [], "text": "15 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

15 mg = 2 NASAL SPRAY DEVICESDEVICES SPRAY ONE TIME ONLY

{ "type": "p", "children": [], "text": "15 mg = 2 NASAL SPRAY DEVICESDEVICES SPRAY ONE TIME ONLY" }

Do NOT open blister packs ortest nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs ortest nasal sprays before use." }

Contains 5 blister packs (5 doses). Each blister pack contains 2 nasal spray devices. 2 devices contain 1 dose (15 mg).

{ "type": "p", "children": [], "text": "Contains 5 blister packs (5 doses). Each blister pack contains 2 nasal spray devices. 2 devices contain 1 dose (15 mg)." }

ATTENTION PHARMACIST: The entire carton is to be dispensed as a unit. Dispense the enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST: The entire carton is to be dispensed as a unit. Dispense the enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }

NDC 72252-510-02Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-510-02Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

10 mg

{ "type": "p", "children": [], "text": "10 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

10 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY

{ "type": "p", "children": [], "text": "10 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY" }

Do NOT open blister packs ortest nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs ortest nasal sprays before use." }

This box contains 2 blister packs.Each blister pack contains 1 nasal spray device.1 device contains 1 dose (10 mg)

{ "type": "p", "children": [], "text": "This box contains 2 blister packs.Each blister pack contains 1 nasal spray device.1 device contains 1 dose (10 mg)" }

ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }

NDC 72252-510-05Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-510-05Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

10 mg

{ "type": "p", "children": [], "text": "10 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

10 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY

{ "type": "p", "children": [], "text": "10 mg = 1 NASAL SPRAY DEVICEDEVICE SPRAYS ONE TIME ONLY" }

Do NOT open blister packs or test nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs or test nasal sprays before use." }

Contains 5 blister packs (5 doses). Each blister pack contains 1 nasal spray device. 1 device contains 1 dose (10 mg).

{ "type": "p", "children": [], "text": "Contains 5 blister packs (5 doses). Each blister pack contains 1 nasal spray device. 1 device contains 1 dose (10 mg)." }

ATTENTION PHARMACIST: The entire carton is to be dispensed as a unit. Dispense the enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST: The entire carton is to be dispensed as a unit. Dispense the enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }

NDC 72252-520-04Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-520-04Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

20 mg

{ "type": "p", "children": [], "text": "20 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

20 mg = 2 NASAL SPRAY DEVICESDEVICES SPRAY ONE TIME ONLY

{ "type": "p", "children": [], "text": "20 mg = 2 NASAL SPRAY DEVICESDEVICES SPRAY ONE TIME ONLY" }

Do NOT open blister packs ortest nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs ortest nasal sprays before use." }

This box contains 2 blister packs.Each blister pack contains 2 nasal spray devices.2 devices contain 1 dose (20 mg)

{ "type": "p", "children": [], "text": "This box contains 2 blister packs.Each blister pack contains 2 nasal spray devices.2 devices contain 1 dose (20 mg)" }

ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST:The entire carton is to be dispensed as a unit. Dispensethe enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }

NDC 72252-520-10 Rx Only

{ "type": "p", "children": [], "text": "NDC 72252-520-10 Rx Only" }

VALTOCO® (diazepam nasal spray) CIV

{ "type": "p", "children": [], "text": "VALTOCO®\n (diazepam nasal spray) CIV" }

20 mg

{ "type": "p", "children": [], "text": "20 mg" }

FOR NASAL USE ONLY.

{ "type": "p", "children": [], "text": "FOR NASAL USE ONLY." }

20 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY

{ "type": "p", "children": [], "text": "20 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY" }

Do NOT open blister packs or test nasal sprays before use.

{ "type": "p", "children": [], "text": "Do NOT open blister packs or test nasal sprays before use." }

Contains 5 blister packs (5 doses). Each blister pack contains 2 nasal spray devices. 2 devices contain 1 dose (20 mg).

{ "type": "p", "children": [], "text": "Contains 5 blister packs (5 doses). Each blister pack contains 2 nasal spray devices. 2 devices contain 1 dose (20 mg)." }

ATTENTION PHARMACIST: The entire carton is to be dispensed as a unit. Dispense the enclosed medication guide to the patient.

{ "type": "p", "children": [], "text": "ATTENTION PHARMACIST: The entire carton is to be dispensed as a unit. Dispense the enclosed medication guide to the patient." }

Check product expiration date before use.

{ "type": "p", "children": [], "text": "Check product expiration date before use." }