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WARNING
RISKS FROM CONCOMITANT USE WITH OPIOIDS
Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
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. 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.
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.
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 and Patient Counseling Information].
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.
Table 1: Recommended Dose Based on Age
| Age (Years) | Recommended Dose |
| 2 through 5 | 0.5 mg/kg |
| 6 through 11 | 0.3 mg/kg |
| 12 and older | 0.2 mg/kg |
Table 2: Recommended Dosage and Administration for Adults and Pediatric Patients 2 Years of Age and Older
| Dose Based on Age and Weight | Administration | ||||
| 2 to 5 Years of Age (0.5 mg/kg) | 6 to 11 Years of Age (0.3 mg/kg) | 12 Years of Age and Older (0.2 mg/kg) | Dose (mg) | Number of Nasal Spray Devices | Number of Sprays |
| Weight (kg) | |||||
| 6 to 11 | 10 to 18 | 14 to 27 | 5 | One 5 mg device | One spray in one nostril |
| 12 to 22 | 19 to 37 | 28 to 50 | 10 | One 10 mg device | One spray in one nostril |
| 23 to 33 | 38 to 55 | 51 to 75 | 15 | Two 7.5 mg devices | One spray in each nostril |
| 56 to 74 | 76 and up | 20 | Two 10 mg devices | One spray in each nostril | |
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.
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. Page 5 of 27
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).
Table 5: Available Packaging Configurations
| Description | Contents | NDC |
| Each Carton Contains 2 Doses | ||
| 5 mg carton | 2 individual blister packs, each containing one 5 mg nasal spray device | 72252-505-02 |
| 10 mg carton | 2 individual blister packs, each containing one 10 mg nasal spray device | 72252-510-02 |
| 15 mg carton | 2 individual blister packs, each containing two 7.5 mg nasal spray devices | 72252-515-04 |
| 20 mg carton | 2 individual blister packs, each containing two 10 mg nasal spray devices | 72252-520-04 |
| Each Carton Contains 5 Doses | ||
| 5 mg carton | 5 individual blister packs, each containing one 5 mg nasal spray device | 72252-505-05 |
| 10 mg carton | 5 individual blister packs, each containing one 10 mg nasal spray device | 72252-510-05 |
| 15 mg carton | 5 individual blister packs, each containing two 7.5 mg nasal spray devices | 72252-515-10 |
| 20 mg carton | 5 individual blister packs, each containing two 10 mg nasal spray devices | 72252-520-10 |
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 25oC (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.
Distributed by: Neurelis, Inc. San Diego, CA 92121 USA. Revised: Apr 2025
The following serious adverse reactions are discussed elsewhere in the labeling:
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.
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], 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.
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
| Adverse Reaction | Diazepam Rectal Gel N=101 % |
Placebo N=104 % |
| Somnolence | 23 | 8 |
| Headache | 5 | 4 |
| Diarrhea | 4 | <1 |
| Ataxia | 3 | <1 |
| Dizziness | 3 | 2 |
| Euphoria | 3 | 0 |
| Incoordination | 3 | 0 |
| Rash | 3 | 0 |
| Asthma | 2 | 0 |
| Vasodilation | 2 | 0 |
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%).
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]. 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].
Potential interactions may occur when diazepam is given concurrently with agents that affect CYP2C19 and CYP3A4 activity.
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 (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.
Included as part of the PRECAUTIONS section.
Concomitant use of benzodiazepines, including VALTOCO, and opioids may result in profound sedation, respiratory depression, coma, and death [see DRUG INTERACTIONS]. 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].
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.
The continued use of benzodiazepines may lead to clinically significant physical dependence. Although VALTOCO is indicated only for intermittent use [see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION], 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].
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].
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.
Table 3: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
| Indication | Placebo Patients with Events/1000 Patients | Drug Patients with Events per 1000 Patients | Relative Risk: Incidence of Drug Events in Drug Patients /Incidence in Placebo Patients | Risk Difference: Additional Drug Patients with Events per 1000 Patients |
| Epilepsy | 1.0 | 3.4 | 3.5 | 2.4 |
| Psychiatric | 5.7 | 8.5 | 1.5 | 2.9 |
| Other | 1.0 | 1.8 | 1.9 | 0.9 |
| Total | 2.4 | 4.3 | 1.8 | 1.9 |
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing 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]. 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. Page 8 of 27
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].
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
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].
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 and Drug Abuse And Dependence].
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 and Drug Abuse And Dependence].
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].
Advise patients and caregivers on how frequently they can treat successive seizure cluster episodes over time.
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 and Use In Specific Populations]. 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].
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].
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.
The data currently available are inadequate to determine the mutagenic potential of diazepam.
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).
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 https://www.aedpregnancyregistry.org.
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 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.
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].
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.
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.
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, CLINICAL PHARMACOLOGY, and Clinical Studies].
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]. 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. Page 14 of 27
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].
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.
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 and DOSAGE AND ADMINISTRATION], 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]. 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].
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 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]. 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.
Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
VALTOCO nasal spray is contraindicated in patients with:
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.
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.
Both diazepam and its major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).
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, 3hydroxydiazepam (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.
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].
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.
The pharmacokinetics of diazepam have not been studied in subjects with renal 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. Page 19 of 27
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.
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].
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.
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
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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
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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.
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.
Figure 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - Second Study
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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.
VALTOCO®
(val-toe-koe)
(diazepam nasal spray)
What is the most important information I should know about VALTOCO?
Do not drive or operate heavy machinery until you know how taking VALTOCO with opioids affects you.
How can I watch for early symptoms of suicidal thoughts or actions?
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.
What is VALTOCO?
Do not use VALTOCO if you:
Before using VALTOCO, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, 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.
How should I use VALTOCO?
What should I do after I give VALTOCO?
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.
A second dose should not be given if there is concern about the person's breathing, they need help with their breathing, or have extreme drowsiness.
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.
What should I avoid while using VALTOCO?
See “What is the most important information I should know about VALTOCO?”
What are the possible side effects of VALTOCO?
VALTOCO may cause serious side effects, including:
The most common side effects of VALTOCO include:
These are not all of the possible side effects of VALTOCO. Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
How should I store VALTOCO?
General information about the safe and effective use of VALTOCO.
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.
What are the ingredients in VALTOCO?
Active ingredient: diazepam
Inactive ingredients: benzyl alcohol, dehydrated alcohol, n-dodecyl beta-D-maltoside, and vitamin E.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
