Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 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 16.2 Storage and Handling 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.; PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 2 Doses NDC 72252-505-02 Rx Only VALTOCO ® (diazepam nasal spray) CIV 5 mg FOR NASAL USE ONLY. 5 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 2 Doses; PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 5 Doses NDC 72252-505-05 Rx Only VALTOCO ® (diazepam nasal spray) CIV 5 mg FOR NASAL USE ONLY. 5 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY 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 (5 mg). 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. PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 5 Doses; PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 2 Doses NDC 72252-515-04 Rx Only VALTOCO ® (diazepam nasal spray) CIV 15 mg FOR NASAL USE ONLY. 15 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 2 Doses; PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 5 Doses NDC 72252-515-10 Rx Only VALTOCO ® (diazepam nasal spray) CIV 15 mg FOR NASAL USE ONLY. 15 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY 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 (15 mg). 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. PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 5 Doses; PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 2 Doses NDC 72252-510-02 Rx Only VALTOCO ® (diazepam nasal spray) CIV 10 mg FOR NASAL USE ONLY. 10 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 2 Doses; PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 5 Doses NDC 72252-510-05 Rx Only VALTOCO ® (diazepam nasal spray) CIV 10 mg FOR NASAL USE ONLY. 10 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY 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). 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. PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 5 Doses; PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 2 Doses NDC 72252-520-04 Rx Only VALTOCO ® (diazepam nasal spray) CIV 20 mg FOR NASAL USE ONLY. 20 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 2 Doses; PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 5 Doses NDC 72252-520-10 Rx Only VALTOCO ® (diazepam nasal spray) CIV 20 mg FOR NASAL USE ONLY. 20 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY 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). 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. PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 5 Doses
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 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 16.2 Storage and Handling 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.
- PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 2 Doses NDC 72252-505-02 Rx Only VALTOCO ® (diazepam nasal spray) CIV 5 mg FOR NASAL USE ONLY. 5 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 2 Doses
- PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 5 Doses NDC 72252-505-05 Rx Only VALTOCO ® (diazepam nasal spray) CIV 5 mg FOR NASAL USE ONLY. 5 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY 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 (5 mg). 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. PRINCIPAL DISPLAY PANEL - 5 mg Device Blister Pack Carton - 5 Doses
- PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 2 Doses NDC 72252-515-04 Rx Only VALTOCO ® (diazepam nasal spray) CIV 15 mg FOR NASAL USE ONLY. 15 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 2 Doses
- PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 5 Doses NDC 72252-515-10 Rx Only VALTOCO ® (diazepam nasal spray) CIV 15 mg FOR NASAL USE ONLY. 15 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY 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 (15 mg). 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. PRINCIPAL DISPLAY PANEL - 15 mg Device Blister Pack Carton - 5 Doses
- PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 2 Doses NDC 72252-510-02 Rx Only VALTOCO ® (diazepam nasal spray) CIV 10 mg FOR NASAL USE ONLY. 10 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 2 Doses
- PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 5 Doses NDC 72252-510-05 Rx Only VALTOCO ® (diazepam nasal spray) CIV 10 mg FOR NASAL USE ONLY. 10 mg = 1 NASAL SPRAY DEVICE DEVICE SPRAYS ONE TIME ONLY 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). 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. PRINCIPAL DISPLAY PANEL - 10 mg Device Blister Pack Carton - 5 Doses
- PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 2 Doses NDC 72252-520-04 Rx Only VALTOCO ® (diazepam nasal spray) CIV 20 mg FOR NASAL USE ONLY. 20 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY Do NOT open blister packs or test 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) 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. PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 2 Doses
- PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 5 Doses NDC 72252-520-10 Rx Only VALTOCO ® (diazepam nasal spray) CIV 20 mg FOR NASAL USE ONLY. 20 mg = 2 NASAL SPRAY DEVICES DEVICES SPRAY ONE TIME ONLY 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). 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. PRINCIPAL DISPLAY PANEL - 20 mg Device Blister Pack Carton - 5 Doses
Overview
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 C 16 H 13 ClN 2 O 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. Chemical Structure
Indications & Usage
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. VALTOCO is a benzodiazepine 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. ( 1 )
Dosage & Administration
Administer VALTOCO by the nasal route only. ( 2.3 ) Dosage is dependent on the patient's age and weight. ( 2.2 ) Initial Dose: VALTOCO 5 mg and 10 mg doses are administered as a single spray intranasally into one nostril. Administration of 15 mg and 20 mg doses requires two nasal spray devices, one spray into each nostril. ( 2.2 ) Second Dose: A second dose, when required, may be administered at least 4 hours after the initial dose. If administered, use a new blister pack. ( 2.2 ) Maximum Dosage and Treatment Frequency: Do not use more than 2 doses to treat a single episode. It is recommended that VALTOCO be used to treat no more than one episode every five days and no more than five episodes per month. ( 2.2 ) 2.1 Instructions Prior to Dosing 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) ]. 2.2 Dosing 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 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. 2.3 Important Administration Instructions 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.
Warnings & Precautions
CNS Depression: Monitor for central nervous system (CNS) depression. May cause an increased CNS-depressant effect when used with alcohol or other CNS depressants. ( 5.4 , 7.2 ) Suicidal Behavior and Ideation: Monitor patients for suicidal ideation and behavior. ( 5.5 ) Glaucoma: 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. ( 4 , 5.6 ) Neonatal Sedation and Withdrawal Syndrome: VALTOCO use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.7 , 8.1 ) 5.1 Risk of Concomitant Use with Opioids 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. 5.2 Abuse, Misuse, and Addiction 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. 5.3 Dependence and Withdrawal Reactions After Use of VALTOCO More Frequently Than Recommended 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) ] . 5.4 CNS Depression 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. 5.5 Suicidal Behavior and Ideation 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. 5.6 Glaucoma 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. 5.7 Neonatal Sedation and Withdrawal Syndrome 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. 5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative 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) ].
Boxed Warning
RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ] . The use of benzodiazepines, including VALTOCO, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing VALTOCO and throughout treatment, assess each patient's risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2) ]. The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. 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 may precipitate acute withdrawal reactions, which can be life-threatening. 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) ]. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. ( 5.1 , 7.1 ) The use of benzodiazepines, including VALTOCO, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing VALTOCO and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. ( 5.2 ) Although VALTOCO is indicated only for intermittent use ( 1 , 2 ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of VALTOCO may precipitate acute withdrawal reactions, which can be life-threatening. For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO. ( 5.3 )
Contraindications
VALTOCO nasal spray is contraindicated in patients with: Known hypersensitivity to diazepam Acute narrow angle glaucoma [see Warnings and Precautions (5.6) ] Hypersensitivity to diazepam. ( 4 ) Acute narrow-angle glaucoma. ( 4 )
Adverse Reactions
The following serious adverse reactions are discussed elsewhere in the labeling: Risk of Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions After Use of VALTOCO More Frequently Than Recommended [see Warnings and Precautions (5.3) ] CNS depression [see Warnings and Precautions (5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5) ] Glaucoma [see Warnings and Precautions (5.6) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.7) ] Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.8) ]. The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. 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 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.
Drug Interactions
CYP2C19 and CYP3A4 Inhibitors: Elimination of diazepam could be decreased with concurrent administration; therefore, adverse reactions with VALTOCO may be increased. ( 7.3 ) Inducers of CYP2C19 and CYP3A4 Inducers: Exposure of diazepam with concurrent administration may be decreased; therefore, efficacy with VALTOCO may be decreased. ( 7.3 ) 7.1 Effect of Concomitant Use of Benzodiazepines and Opioids 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. 7.2 CNS Depressants and Alcohol 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) ]. 7.3 Effect of Other Drugs on VALTOCO Metabolism 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. 7.4 Effect of VALTOCO on the Metabolism of Other Drugs 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.
Storage & Handling
16.2 Storage and Handling 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.
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