Sympazan clobazam 5 mg Film, 60-count — NDC 10094-205-60 (Billing 10094-0205-60)
This is a package of 60 films of Sympazan clobazam 5 mg Film from Aquestive Therapeutics, marketed since Nov 2018 and currently FDA-listed; retail pharmacies pay about $16.40 per film (NADAC). It is this product's only package size.
Other active recalls for Clobazam (different manufacturers) — 3 · tap to view
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 078861
- GCN: 45264
- GPI-14 (Medi-Span): 72100007008205
- HICL (First Databank): 006536
- AHFS class code: 28:12.08.00
- RxCUI (RxNorm): 2058253
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Benzodiazepine class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
Clobazam is used with other medication(s) to control seizures in adults and children 2 years of age and older who have Lennox-Gastaut syndrome (a disorder that causes seizures and often causes developmental delays). Clobazam is in a class of medications called benzodiazepines. It works by decreasing abnormal electrical activity in the brain.
Read the full MedlinePlus article ↗- Clobazam is an add-on medicine for seizures caused by Lennox-Gastaut syndrome in people 2 years and older. It is used along with other seizure medicines, not on its own.
- Take it by mouth exactly as prescribed, usually split into two doses a day if your dose is above the lowest amount. You can take it with or without food. Tablets can be swallowed w...
- No. Stopping suddenly can cause withdrawal reactions, including seizures, and can be life-threatening. Your prescriber will lower the dose slowly over time.
- Sleepiness is the most common. You may also notice tiredness, fever, constipation, drooling, irritability, or poor balance. Call your doctor right away for a rash, breathing troubl...
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Clobazam — tap one for details:
Clobazam may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $16.403 | $984.19 / 60 film |
| Medicaid paysCMS SDUD · 12 mo | $16.18 | $970.90 / 60 film |
| Medicare drug plans payPart D · Q2 2026 | $16.86 | $1,011.59 / 60 film |
Where does this data come from?
- CMS NADAC weekly file · file of Sep 30, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Marketing end | Status |
|---|---|---|---|---|
| 10094-0205-60 You're viewing this Main listing | 60 POUCH in 1 PACKAGE / 1 FILM in 1 POUCH | 2018-11-01 | — | Active |
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Sympazan 5 mgthis 10094-0205-60 | Aquestive | 60 films | $16.403 | — | Availability likely | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file · file of Sep 30, 2026
Availability & generic status
We did not find an FDA-approved generic match for this exact strength, form and route. Patent/protection dates below may affect future generic timing.
Why the date isn’t exact: Generic timing can change because patents may be challenged, settled, licensed, added, removed, or worked around with a narrower label — and FDA approval does not always mean a pharmacy can get the generic today.
🛈 What do these terms mean?
- Patent
- Legal protection listed in the Orange Book that may delay generic approval or launch. Issued by the U.S. Patent & Trademark Office.
- Substance patent
- Covers the active drug molecule itself — the hardest to design around. A generic generally can’t launch until it expires.
- Formulation (product) patent
- Covers a specific formulation or dosage form. A generic can sometimes work around it with a different formulation.
- Method-of-use patent
- A patent covering one specific approved use of the drug — not necessarily the whole molecule. A generic can sometimes launch with a “skinny label” that carves out the protected use and keeps the others.
- Skinny label
- A generic label that omits a still-patented use when the FDA allows it — letting a generic reach the market for the unprotected uses.
- Exclusivity
- FDA-granted marketing protection, separate from patents — e.g. 5-yr new chemical entity, 7-yr orphan drug, or a +6-month pediatric extension.
- Paragraph IV
- A generic applicant’s formal challenge to a listed patent. It can potentially lead to earlier generic entry, but often involves litigation or a settlement.
- RLD / RS
- Reference Listed Drug — the brand product the FDA uses as the reference for generic applications. Reference Standard — the product the FDA expects generics to compare against in bioequivalence testing.
- TE / AB rating
- FDA therapeutic-equivalence rating. An AB rating generally means the FDA considers a generic therapeutically equivalent to — and substitutable for — the brand.
- LOE (loss of exclusivity)
- The latest patent or exclusivity currently listed — the loss-of-exclusivity / latest-listed-protection date shown on this page. Paragraph-IV challenges and settlements can move the real date earlier; FDA approval and a manufacturer’s decision to market can move it later.
Built from the FDA Orange Book. The bars above are scaled to each protection’s expiry; the red LOE marker is the last one to lapse.
| Patent | Type | Use code | Expires |
|---|---|---|---|
| US 12403090 ↗ | Method of use | U-724 | Sep 5, 2039 |
| US 12403090 ↗ | Method of use | U-724 | Sep 5, 2039 |
| US 12290597 ↗ | Method of use | U-724 | Sep 5, 2039 |
| US 12290597 ↗ | Method of use | U-724 | Sep 5, 2039 |
| US 11541002 ↗ | Method of use | U-724 | Jan 31, 2040 |
| US 11541002 ↗ | Method of use | U-724 | Jan 31, 2040 |
| US 11541002 ↗ | Method of use | U-724 | Jan 31, 2040 |
Is there a generic version of SYMPAZAN 5 MG FILM?
The FDA approved a generic — why can’t I get it at my pharmacy yet?
Why do different websites show different generic release dates?
What does “FDA listed” mean?
What does a patent or protection date mean here?
What does “current Orange Book estimate” mean?
Can a generic come out before the last patent expires?
Can a generic come out after the listed dates?
What is the difference between patents and exclusivity?
Why are there multiple patent dates?
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII 2968PHW8QP
A weak organic acid derived from citrus fruits or made through fermentation. It works as a buffer to control pH, a preservative to extend shelf life, and a flavoring agent in medications.
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UNII C4YAD5F5G6
A natural oil-derived emulsifier made from glycerin and oleic acid. It helps mix oil and water-based ingredients together in the medicine and may improve how the body absorbs certain drugs.
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UNII 3NXW29V3WO
Hypromellose is a plant-based thickener made from cellulose. It's used in medicines as a binder to hold ingredients together, a coating for tablets, and a thickener for liquids.
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UNII D65DG142WK
Maltitol is a sugar alcohol made by hydrogenating maltose. It's used as a sweetener and filler in medicines to improve taste and add bulk to tablets and capsules.
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UNII 11628IH70O
Polyethylene oxide is a synthetic polymer derived from ethylene. In medicines, it acts as a binder to hold ingredients together, a thickener to adjust texture, and a disintegrant to help the tablet or capsule break apart for absorption.
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UNII 22ADO53M6F
A mineral salt derived from phosphoric acid, used as a buffer to maintain the pH balance of the medication and help stabilize the active ingredients.
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UNII 96K6UQ3ZD4
Sucralose is a synthetic sweetener made from sugar. It's added to medicines to improve taste without adding calories, helping make bitter or unpleasant-tasting drugs easier to take.
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UNII 059QF0KO0R
Water is a liquid solvent that dissolves and mixes ingredients together in liquid medicines, syrups, and injections. It helps distribute the active drug evenly throughout the product.
8 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
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Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
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 in 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 SYMPAZAN, 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 SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2) ]. The continued use of benzodiazepines, including SYMPAZAN, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose.
Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN or reduce the dosage [see Dosage and Administration (2.2) and 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.
Reserve concomitant prescribing of these drugs in 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 ( 5.1 , 7.1 ).
The use of benzodiazepines, including SYMPAZAN, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction ( 5.2 ). Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use may precipitate acute withdrawal reactions, which can be life-threatening.
To reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN ( 2.2 , 5.3 ).
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE SYMPAZAN ® is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older. SYMPAZAN ® is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients 2 years of age or older ( 1 ).
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION For doses above 5 mg/day, administer in two divided doses ( 2.1 ) Patients weighing 30 kg or less: Initiate at 5 mg daily, and titrate as tolerated up to 20 mg daily ( 2.1 ) Patients weighing greater than 30 kg: Initiate at 10 mg daily, and titrate as tolerated up to 40 mg daily ( 2.1 ) Dosage adjustment is needed in following groups: ○ Geriatric patients ( 2.4 , 8.5 ) ○ Known CYP2C19 poor metabolizers ( 2.5 ) ○ Mild or moderate hepatic impairment; no information for severe hepatic impairment ( 2.6 , 8.8 ) Can be taken with or without food ( 2.3 ) Do not administer with liquids ( 2.3 )
2.1Dosing Information A daily dose of SYMPAZAN ® greater than 5 mg should be administered in divided doses twice daily; a 5 mg daily dose can be administered as a single dose. Dose patients according to body weight. Individualize dosing within each body weight group, based on clinical efficacy and tolerability.
Each dose in Table 1 (e.g., 5 to 20 mg in 30 kg or less weight group) has been shown to be effective, although effectiveness increases with increasing dose [see Clinical Studies (14) ]. Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazam and its active metabolite require 5 and 9 days, respectively, to reach steady-state. Table 1: Recommended Total Daily Dosing by Weight Group 30 kg or Less Body Weight Greater than 30 kg Body Weight Starting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg
2.2Discontinuation or Dosage Reduction of SYMPAZAN To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue SYMPAZAN or reduce the dosage . Taper by decreasing the total daily dosage by 5-10 mg/day on a weekly basis until discontinued. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.
Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3) ].
2.3Important Administration Instructions Instruct patients and/or caregivers to read the “Instructions for Use” carefully for complete directions on how to properly dose and administer SYMPAZAN ® oral films. Apply SYMPAZAN ® on top of the tongue where it adheres and dissolves. SYMPAZAN® oral film can be taken with or without food [see Clinical Pharmacology (12.3) ].
Do not administer with liquids. As the film dissolves, saliva should be swallowed in a normal manner, but the patient should refrain from chewing, spitting or talking. Only one oral film should be taken at a time; if a second film is needed to complete the dosage, it should not be taken until the first film has completely dissolved.
2.4Dosage Adjustments in Geriatric Patients Plasma concentrations at any given dose are generally higher in geriatric patients [see Clinical Pharmacology (12.3) ]. Therefore, the starting dosage should generally be 5 mg/day for all geriatric patients. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated.
If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 [see Use in Specific Populations (8.5) ].
2.5Dosage Adjustments in CYP2C19 Poor Metabolizers In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased [see Clinical Pharmacology (12.5) ]. Therefore, the starting dosage should be 5 mg/day in patients known to be CYP2C19 poor metabolizers. Then proceed slowly with dose escalation; titrate according to weight, but to half the dosage presented in Table 1, as tolerated.
If necessary and based upon clinical response, an additional titration to the maximum dosage (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 [see Use in Specific Populations (8.6) ]. 2.6… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS SYMPAZAN ® Oral Film: Thin, white, rectangular, orally dissolving film strips: 5 mg imprinted with C5 10 mg imprinted with C10 20 mg imprinted with C20 Oral Film: 5 mg, 10 mg and 20 mg ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS SYMPAZAN ® is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients. Hypersensitivity reactions have included serious dermatological reactions [see Warnings and Precautions (5.6) ]. History of hypersensitivity to the drug or its ingredients ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Somnolence or Sedation: Monitor for central nervous system (CNS) depression. Risk may be increased with concomitant use of other CNS depressants ( 5.4 , 5.5 ) Serious Dermatological Reactions (including Stevens-Johnson Syndrome and toxic epidermal necrolysis): Discontinue SYMPAZAN ® at first sign of rash unless the rash is clearly not drug-related ( 5.6 ) Drug Reaction with Eosinophilia and Systemic Symptoms (Dress)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.7 ) Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behaviors ( 5.8 ) Neonatal Sedation and Withdrawal Syndrome: SYMPAZAN use during pregnancy can result in neonatal sedation and/or neonatal withdrawal ( 5.9 , 8.1 )
5.1Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including SYMPAZAN ® , and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids in 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 SYMPAZAN ® 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 SYMPAZAN ® is used with opioids [see Drug Interactions (7.1) ].
5.2Abuse, Misuse, and Addiction The use of benzodiazepines, including SYMPAZAN, 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 SYMPAZAN and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of SYMPAZAN, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of SYMPAZAN along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; 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.
5.3Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN or reduce the dosage [see Dosage and Administration (2.2) ]. 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, including SYMPAZAN, may lead to clinically significant physical dependence.
Abrupt discontinuation or rapid dosage reduction of SYMPAZAN after continued use, 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 [se… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include the following: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3) ] Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants [see Warnings and Precautions (5.4) ] Somnolence or Sedation [see Warnings and Precautions (5.5) ] Serious Dermatological Reactions [see Contraindications (4) , Warnings and Precautions (5.6) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.7) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.8) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.9) ] Adverse reactions that occurred at least 10% more frequently than placebo in any clobazam dose included constipation, somnolence or sedation, pyrexia, lethargy, and drooling ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience 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 following adverse events have been reported in clinical trials of patients treated with clobazam, the active ingredient of SYMPAZAN ® . During its development for the adjunctive treatment of seizures associated with LGS, clobazam was administered to 333 healthy volunteers and 300 patients with a current or prior diagnosis of LGS, including 197 patients treated for 12 months or more.
The conditions and duration of exposure varied greatly and included single- and multiple-dose clinical pharmacology studies in healthy volunteers and two double-blind studies in patients with LGS (Study 1 and 2) [see Clinical Studies (14) ]. Only Study 1 included a placebo group, allowing comparison of adverse reaction rates on clobazam at several doses to placebo. Adverse Reactions Leading to Discontinuation in an LGS Placebo Controlled Clinical Trial (Study 1) The adverse reactions associated with clobazam treatment discontinuation in ≥1% of patients in decreasing order of frequency included lethargy, somnolence, ataxia, aggression, fatigue, and insomnia.
Most Common Adverse Reactions in an LGS Placebo Controlled Clinical Trial (Study 1) Table 3 lists the adverse reactions that occurred in ≥5% of clobazam-treated patients (at any dose), and at a rate greater than placebo-treated patients, in the randomized, double-blind, placebo-controlled, parallel group clinical study of adjunctive AED therapy for 15 weeks (Study 1). Table 3: Adverse Reactions Reported for ≥5% of Patients and More Frequently than Placebo in Any Treatment Group Clobazam Dose Level All Clobazam N=179 % Placebo N=59 % Low a N=58 % Medium b N=62 % High c N=59 % Gastrointestinal Disorders Vomiting 5 9 5 7 7 Constipation 0 2 2 10 5 Dysphagia 0 0 0 5 2 General Disorders and Administration Site Conditions Pyrexia 3 17 10 12 13 Irritability 5 3 11 5 7 Fatigue 2 5 5 3 5 Infections and Infestations Upper respiratory tract infection 10 10 13 14 12 Pneumonia 2 3 3 7 4 Urinary tract infection 0 2 5 5 4 Bronchitis 0 2 0 5 2 Metabolism and Nutrition Disorders Decreased appetite 3 3 0 7 3 Increased appetite 0 2 3 5 3 Nervous System Disorders Somnolence or Sedation 15 17 27 32 26 Somnolence 12 16 24 25 22 Sedation 3 2 3 9 5 Lethargy 5 10 5 15 10 Drooling 3 0 13 14 9 Ataxia 3 3 2 10 5 Psychomotor hyperactivity 3 3 3 5 4 Dysarthria 0 2 2 5 3 Psychiatric Disorders Aggression 5 3 8 14 8 Insomnia 2 2 5 7 5 Respiratory Disorders Cough 0 3 5 7 5 a Maximum daily dose of 5 mg for ≤30 kg body weight; 10 mg for >30 kg body weight b Maxi… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Alcohol: Increases blood levels of clobazam by about 50% ( 7.2 ) Drugs metabolized by CYP2D6: Lower doses of these drugs may be required when used concomitantly with SYMPAZAN ® ( 7.3 ) Strong or Moderate CYP2C19 Inhibitors: Dosage adjustment of SYMPAZAN ® may be necessary ( 7.4 ) Cannabidiol: May increase risk of SYMPAZAN-related adverse reactions; consider dosage adjustment if this occurs ( 7.4 )
7.1Opioids 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.
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) ].
7.2CNS Depressants and Alcohol Concomitant use of SYMPAZAN ® with other CNS depressants may increase the risk of sedation and somnolence [see Warnings and Precautions (5.4) ]. Alcohol, as a CNS depressant, will interact with SYMPAZAN ® in a similar way and also increases clobazam's maximum plasma exposure by approximately 50%. Therefore, caution patients or their caregivers against simultaneous use with other CNS depressant drugs or alcohol, and caution that the effects of other CNS depressant drugs or alcohol may be potentiated [see Warnings and Precautions (5.4) ].
7.3Effect of SYMPAZAN ® on Other Drugs Hormonal Contraceptives SYMPAZAN ® is a weak CYP3A4 inducer. As some hormonal contraceptives are metabolized by CYP3A4, their effectiveness may be diminished when given with SYMPAZAN ® . Additional non-hormonal forms of contraception are recommended when using SYMPAZAN ® [see Clinical Pharmacology (12.3) , Patient Counseling Information (17) ].
Drugs Metabolized by CYP2D6 SYMPAZAN ® inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary [see Clinical Pharmacology (12.3) ].
7.4Effect of Other Drugs on SYMPAZAN ® Strong and Moderate Inhibitors of CYP2C19 Coadministration with strong or moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam, the active metabolite of clobazam. This may increase the risk of dose-related adverse reactions. Dosage adjustment of SYMPAZAN ® may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole) [see Clinical Pharmacology (12.3) ].
Effect of Cannabidiol on SYMPAZAN ® Coadministration of cannabidiol, a CYP3A4 and CYP2C19 substrate and a CYP2C19 inhibitor, with clobazam may increase the risk of clobazam-related adverse reactions [ see Warnings and Precautions (5.4, 5.5) , Clinical Pharmacology (12.3) ]. Consider a reduction in dosage of cannabidiol or clobazam if adverse reactions known to occur with SYMPAZAN are experienced.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 )
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN ® , during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking SYMPAZAN ® enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at 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 (5.9) 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 Data ). Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [ see Animal Data ].
Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. 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%-4% and 15% -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 SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.
Monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9) ]. 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 In a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses.
The low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day. Oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose.
Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low effect dose for embryofetal developmental toxici… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as SYMPAZAN ® , during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking SYMPAZAN ® enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or online at 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 (5.9) 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 Data ). Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients [ see Animal Data ].
Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. 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%-4% and 15% -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 SYMPAZAN during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems.
Monitor neonates exposed to SYMPAZAN during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.9) ]. 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 In a study in which clobazam (0, 150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryofetal mortality and incidences of fetal skeletal variations were increased at all doses.
The low-effect dose for embryofetal developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, lower than those in humans at the maximum recommended human dose (MRHD) of 40 mg/day. Oral administration of clobazam (0, 10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryofetal mortality at the high dose.
Incidences of fetal variations were increased at all doses. The highest dose tested was associated with maternal toxicity (ataxia and decreased activity). The low effect dose for embryofetal developmental toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmeth… [Excerpted — this section continues on DailyMed.]
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in pediatric patients 2 years of age and older have been established in two adequate and well-controlled studies [see Clinical Studies (14) ]. Safety and effectiveness in patients less than 2 years of age have not been established. Juvenile Animal Data In a study in which clobazam (0, 4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose.
The effect on bone density, but not on behavior, was reversible when drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients.
🧓 Geriatric Use ▾
8.5Geriatric Use Clinical studies of clobazam did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. However, elderly subjects appear to eliminate clobazam more slowly than younger subjects based on population pharmacokinetic analysis. For these reasons, dosage modification is recommended [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ].
🆘 Overdosage ▾
10 OVERDOSAGE 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. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABA A receptor.
12.2Pharmacodynamics Effects on Electrocardiogram The effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator-blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern.
Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent.
12.3Pharmacokinetics SYMPAZAN ® Oral Films at single doses of 10 mg and 20 mg clobazam have been shown to be bioequivalent (C m a x and AUC) to clobazam tablets at equivalent doses. Following single-dose administration of SYMPAZAN ® , peak plasma levels (C max ) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-20 mg. Based on a population pharmacokinetic analysis with clobazam tablets, the pharmacokinetics of clobazam are linear from 5-160 mg/day.
Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t 1/2 ) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively. Absorption The time to peak concentrations (T m a x ) of SYMPAZAN ® clobazam oral film under fasted conditions ranged from 0.33 to 4.0 hours after single-dose administration.
The administration of clobazam tablets with food does not affect absorption. Although not studied, the oral bioavailability of SYMPAZAN ® oral film is unlikely to be affected under fed conditions. Distribution Clobazam is lipophilic and distributes rapidly throughout the body.
The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively. Metabolism and Excretion Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug.
The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency.
N-desmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam [see Clinical Pharmacology (12.5) ]. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers. Pharmacokinetics in Specific Populations Age Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages less than 64).
Dosing should be adjusted in the elderly [see Dosage and Administration (2.4) ]. Sex Population pharmacokinetic analyses showed no difference in t… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABA A receptor.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Each SYMPAZAN ® oral film is a white rectangular film that contains 5 mg, 10 mg or 20 mg of clobazam and printed in black ink either "C5,” "C10" or "C20" on the strip according to their respective strengths and each film is packaged in a pouch (sachet). NDC 10094-205-60: 5 mg oral film, Package of 60 NDC 10094-210-60: 10 mg oral film, Package of 60 NDC 10094-220-60: 20 mg oral film, Package of 60 Store SYMPAZAN ® oral film pouches (sachets) 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].
📋 Description ▾
11 DESCRIPTION SYMPAZAN ® contains clobazam, a benzodiazepine derivative, which is chemically known as 7-Chloro-1-methyl-5-phenyl-1 H -1,5 benzodiazepine-2,4( 3H , 5H )-dione with a molecular formula of C 16 H 13 ClN 2 O 2 , molecular weight of 300.74, and it has the following structural formula: Clobazam is a white or almost white, crystalline powder with a slightly bitter taste. It is slightly soluble in water and sparingly soluble in ethanol. Each SYMPAZAN ® Oral Film contains 5 mg, 10 mg or 20 mg of clobazam and the following inactive ingredients: artificial cooling flavor, citric acid, glycerol monooleate, hypromellose, maltitol, natural and artificial bitter masker, natural raspberry type flavor, polyethylene oxide, purified water, sodium phosphate dibasic, and sucralose.
The following structural formula for SYMPAZANTM contains -clobazam,a benzodiazepine derivative, which is chemically known as 7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4(3H,5H)-dione with a molecular formula of C16H13 ClN2O2 , molecular weight of 300.74.
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ). Risks from Concomitant Use with Opioids Inform patients and caregivers that potentially fatal additive effects may occur if SYMPAZAN ® is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ]. Abuse, Misuse, and Addiction Inform patients that the use of SYMPAZAN, 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 Advise patients or caregivers that abrupt withdrawal of AEDs may increase their risk of seizure. Inform patients that the continued use of SYMPAZAN may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of SYMPAZAN 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. Instruct patients that discontinuation or dosage reduction of SYMPAZAN may require a slow taper [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3) ]. Somnolence or Sedation Advise patients or caregivers to check with their healthcare provider before SYMPAZAN ® is taken with other CNS depressants such as other benzodiazepines, opioids, tricyclic antidepressants, sedating antihistamines, or alcohol [see Warnings and Precautions (5.4 , 5.5) ].
If applicable, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that SYMPAZAN ® does not affect them adversely (e.g., impair judgment, thinking or motor skills). Hypersensitivity Inform patients or caregivers that SYMPAZAN ® is contraindicated in patients with a history of hypersensitivity to the drug or its ingredients [see Warnings and Precautions (5.6) ]. Interactions with Hormonal Contraceptives Counsel women to also use non-hormonal methods of contraception when SYMPAZAN ® is used with hormonal contraceptives and to continue these alternative methods for 28 days after discontinuing SYMPAZAN ® to ensure contraceptive reliability [see Drug Interactions (7.3) , Clinical Pharmacology (12.3) ].
Serious Dermatological Reactions Advise patients or caregivers that serious skin reactions have been reported in patients taking clobazam. Serious skin reactions, including SJS/TEN, may need to be treated in a hospital and may be life-threatening. If a skin reaction occurs while taking SYMPAZAN ® , patients or caregivers should consult with healthcare providers immediately [see Warnings and Precautions (5.6) ].
DRESS/Multiorgan Hypersensitivity Instruct patients and caregivers that a fever or rash associated with signs of other organ system involvement (e.g., lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately. SYMPAZAN should be discontinued immediately if a serious hypersensitivity reaction is suspected [see Warnings and Precautions ( 5.7) ] . Suicidal Thinking and Behavior Counsel patients, their caregivers, and their families that AEDs, including SYMPAZAN ® , 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, b… [Excerpted — this section continues on DailyMed.]
💬 Medication Guide ▾
MEDICATION GUIDE SYMPAZAN ® (SYM-pa-zan) (clobazam) oral film, CIV What is the most important information I should know about SYMPAZAN? SYMPAZAN is a benzodiazepine medicine. Taking b enzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depre ssion), coma, and death .
Get emergency help right away if any of the following happens: ○ shallow or slowed breathing ○ breathing stops (which may lead to the heart stopping) ○ excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking SYMPAZAN with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk for abuse, misuse, and addiction with benzodiazepines, including SYMPAZAN, which can lead to overdose and serious side effects including coma and death. ○ Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including SYMPAZAN.
These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. ○ You can develop an addiction even if you take SYMPAZAN as prescribed by your healthcare provider. ○ Take SYMPAZAN exactly as your healthcare provider prescribed. ○ Do not share your SYMPAZAN with other people. ○ Keep SYMPAZAN in a safe place and away from children.
Physical dependence and withdrawal reactions. SYMPAZAN can cause physical dependence and withdrawal reactions. ○ Do not suddenly stop taking SYMPAZAN. Stopping SYMPAZAN 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.
Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. ○ Some people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, 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. ○ 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. ○ Do not take more SYMPAZAN than prescribed or take SYMPAZAN for longer than prescribed. SYMPAZAN can make you sleepy or dizzy and can slow your thinking and motor skills. ○ Do not drive, operate heavy machinery, or do other dangerous activities until you know how SYMPAZAN affects you. ○ Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking SYMPAZAN without first talking to your healthcare provider.
When taken with alcohol or drugs that cause sleepiness or dizziness, SYMPAZAN may make your sleepiness or dizziness much worse. Serious skin reactions have been seen when SYMPAZAN is taken with other medicines and may require stopping its use. Do not stop taking SYMPAZAN without first talking to your healthcare provider. ○ A serious skin reaction can happen at any time during your treatment with SYMPAZAN, but is more likely to happen within the first 8 weeks of treatment.
These skin reactions may need to be treated right away. ○ Call your healthcare provider immediately if you have skin blisters, rash, sores in mouth, hives or any other allergic reaction. A serious allergic reaction that may affect your skin or other parts of your body such as your liver, kidneys, heart, or blood cell… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics SYMPAZAN ® Oral Films at single doses of 10 mg and 20 mg clobazam have been shown to be bioequivalent (C m a x and AUC) to clobazam tablets at equivalent doses. Following single-dose administration of SYMPAZAN ® , peak plasma levels (C max ) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-20 mg. Based on a population pharmacokinetic analysis with clobazam tablets, the pharmacokinetics of clobazam are linear from 5-160 mg/day.
Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t 1/2 ) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively. Absorption The time to peak concentrations (T m a x ) of SYMPAZAN ® clobazam oral film under fasted conditions ranged from 0.33 to 4.0 hours after single-dose administration.
The administration of clobazam tablets with food does not affect absorption. Although not studied, the oral bioavailability of SYMPAZAN ® oral film is unlikely to be affected under fed conditions. Distribution Clobazam is lipophilic and distributes rapidly throughout the body.
The apparent volume of distribution at steady state was approximately 100 L. The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively. Metabolism and Excretion Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug.
The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency.
N-desmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam [see Clinical Pharmacology (12.5) ]. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers. Pharmacokinetics in Specific Populations Age Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages less than 64).
Dosing should be adjusted in the elderly [see Dosage and Administration (2.4) ]. Sex Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men. Race Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.
Renal Impairment The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CL CR ] >50 to 80 mL/min; N=6) and moderate (CL CR =30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of clobazam 20 mg/day. There were insignificant changes in C max (3-24%) and AUC (≤13%) for clobazam or N-desmethylclobazam in patients with mild or moderate renal impairment compared to patients with normal renal function.
Patients with severe renal impairment or ESRD were not included in this study. Hepatic Impairment There are limited data to characterize the effect of hepatic impairmen… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics Effects on Electrocardiogram The effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator-blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern.
Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent.
🔬 Clinical Studies ▾
14 CLINICAL STUDIES Figure 1: Mean Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1) Figure 2: Drop Seizure Response by Category for Clobazam and Placebo (Study 1)
14.1Demonstration of Pharmacokinetic Equivalence Between SYMPAZAN ® and Clobazam Tablets The efficacy of SYMPAZAN ® is based upon bioavailability studies comparing clobazam tablets to SYMPAZAN ® [see Clinical Pharmacology (12.3) ].
14.2Adjunctive Treatment of Seizures Associated with Lennox-Gastaut Syndrome (LGS) The effectiveness of clobazam for the adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome was established in two multicenter controlled studies (Study 1 and Study 2). Both studies were similar in terms of disease characteristics and concomitant AED treatments. The most common concomitant AED treatments at baseline included: valproate, lamotrigine, levetiracetam, and topiramate.
Study 1 Study 1 (N=238) was a randomized, double-blind, placebo-controlled study consisting of a 4-week baseline period followed by a 3-week titration period and 12-week maintenance period. Patients age 2-54 years with a current or prior diagnosis of LGS were stratified into 2 weight groups (12.5 kg to ≤30 kg or >30 kg) and then randomized to placebo or one of three target maintenance doses of clobazam according to Table 4 . Table 4: Study 1 Total Daily Dose ≤30 kg Body Weight >30 kg Body Weight Low Dose 5 mg daily 10 mg daily Medium Dose 10 mg daily 20 mg daily High Dose 20 mg daily 40 mg daily Doses above 5 mg/day were administered in two divided doses.
The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to 12-week maintenance period. The pre-dosing baseline mean weekly drop seizure frequency was 98, 100, 61, and 105 for the placebo, low-, medium-, and high-dose groups, respectively. Figure 1 presents the mean percent reduction in weekly drop seizures from this baseline.
All dose groups of clobazam were statistically superior (p≤0.05) to the placebo group. This effect appeared to be dose dependent. Figure 1: Mean Percent Reduction from Baseline in Weekly Drop Seizure Frequency (Study 1) Figure 2 shows changes from baseline in weekly drop seizure frequency by category for patients treated with clobazam and placebo in Study 1.
Patients in whom the seizure frequency increased are shown at left as "worse." Patients in whom the seizure frequency decreased are shown in five categories. Figure 2: Drop Seizure Response by Category for Clobazam and Placebo (Study 1) There was no evidence that tolerance to the therapeutic effect of clobazam developed during the 3-month maintenance period. Study 2 Study 2 (N=68) was a randomized, double-blind comparison study of high- and low-dose clobazam, consisting of a 4-week baseline period followed by a 3-week titration period and 4-week maintenance period.
Patients age 2-25 years with a current or prior diagnosis of LGS were stratified by weight, then randomized to either a low or high dose of clobazam, and then entered a 3-week titration period. The primary efficacy measure was the percent reduction in the weekly frequency of drop seizures (atonic, tonic, or myoclonic), also known as drop attacks, from the 4-week baseline period to the 4-week maintenance period. A statistically significantly greater reduction in seizure frequency was observed in the high-dose group compared to the low-dose group (median percent reduction of 93% vs 29%; p<0.05).
🔒 Drug Abuse and Dependence ▾
9 DRUG ABUSE AND DEPENDENCE
9.1Controlled Substance SYMPAZAN ® contains clobazam, a Schedule IV controlled substance.
9.2Abuse SYMPAZAN 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) . The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam.
9.3Dependence Physical Dependence SYMPAZAN may produce physical dependence from continued therapy. 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. Abrupt discontinuation or rapid dosage reduction of benzodiazepines 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) ]. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue SYMPAZAN or reduce the dosage [see Dosage and Administration (2.2) and 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… [Excerpted — this section continues on DailyMed.]
🔒 Controlled Substance ▾
9.1Controlled Substance SYMPAZAN ® contains clobazam, a Schedule IV controlled substance.
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In mice, oral administration of clobazam (0, 6, 12, or 24 mg/kg/day) for 2 years did not result in an increase in tumors. The highest dose tested was approximately 3 times the maximum recommended human dose (MRHD) of 40 mg/day, based on body surface area (mg/m 2 ). In rats, oral administration of clobazam for 2 years resulted in increases in tumors of the thyroid gland (follicular cell adenoma and carcinoma) and liver (hepatocellular adenoma) at the mid and high doses.
The low dose, not associated with an increase in tumors, was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than that in humans at the MRHD. Mutagenesis Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays. Impairment of Fertility In a fertility study in which clobazam (50, 350, or 750 mg/kg/day, corresponding to 12, 84, and 181 times the oral Maximum Recommended Human Dose, MRHD, of 40mg/day based on mg/m 2 body surface) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested.
The no-effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day.
📄 Patient Package Insert ▾
Instructions for Use SYMPAZAN ® (SIM-pa-zan) (clobazam) oral film, CIV Read this Instructions for Use before you start using SYMPAZAN and each time you get a refill. There may be new information. The information does not take the place of talking with your healthcare provider about your medical condition or treatment.
Important Information for Patient and Caregiver: Do not take SYMPAZAN until: ○ you have read and understand these instructions. ○ you have reviewed the steps with your healthcare provider on how to take it. ○ you know the right time, how often, and the dose to take. ○ you feel comfortable with how to use SYMPAZAN. If you are not sure about giving treatment or when to give treatment, call your healthcare provider before using SYMPAZAN . How should I store SYMPAZAN?
Store SYMPAZAN at room temperature between 68°F to 77°F (20°C to 25°C). Keep SYMPAZAN in the foil pouch until you are ready to use. Use right away after opening foil pouch.
Keep SYMPAZAN and all medicines out of the reach of children. How to Use SYMPAZAN: Take only 1 SYMPAZAN film at a time unless instructed differently by your healthcare provider. If a second film is needed to get a full dose of SYMPAZAN, do not take the second film until the first film has completely dissolved.
Place the entire SYMPAZAN oral film on top of the tongue. Check your prescription or contact your healthcare provider if you are not sure about the amount to take. Make sure your hands are clean and dry before handling the SYMPAZAN film.
Check the expiration date printed on the foil pouch. Do not use SYMPAZAN if expired. Step 1.
Open Pouch Fold foil pouch along solid line. Note where the slit is and carefully tear it to open pouch. Step 2.
Remove Film Remove the SYMPAZAN from the foil pouch. Step 3. Place on Tongue Place SYMPAZAN on top of the tongue.
The film will stick to the tongue and begin to dissolve. Step 4. Close Mouth and Swallow Saliva Normally Close mouth.
Swallow saliva normally as SYMPAZAN dissolves. Do not take with liquids. Do not chew, spit, or talk while SYMPAZAN dissolves.
Wash your hands after taking SYMPAZAN. Throw away the empty foil pouch in the regular trash. Manufactured by: Aquestive Therapeutics Warren, NJ 07059 For more information or support about SYMPAZAN: Call 1-800-518-1084 This Instructions for Use has been approved by the U.S.
Food and Drug Administration. Revision Date: 11/2018 Step 1. Open Pouch Step 2.
Remove Film Step 3. Place on Tongue Step 4. Close Mouth and Swallow Saliva Normally
📄 Recent Major Changes ▾
Warning and Precautions ( 5.7 , 5.9 ) 3/2024
📄 Package Label / Principal Display Panel ▾
PRINCIPAL DISPLAY PANEL NDC 10094-205-01 Sympazan (clobazam) Oral film 5 mg Rx Only 1 Oral films PRINCIPAL DISPLAY PANEL NDC 10094-205-01 Sympazan (clobazam) Oral film 5 mg Rx Only 1 Oral films
PRINCIPAL DISPLAY PANEL NDC 10094-205-60 Sympazan (clobazam) Oral film 5 mg Rx Only 60 Oral films PRINCIPAL DISPLAY PANEL NDC 10094-205-60 Sympazan (clobazam) Oral film 5 mg Rx Only 60 Oral films
PRINCIPAL DISPLAY PANEL NDC 10094-210-01 Sympazan (clobazam) Oral film 10 mg Rx Only 1 Oral films PRINCIPAL DISPLAY PANEL NDC 10094-210-01 Sympazan (clobazam) Oral film 10 mg Rx Only 1 Oral films
PRINCIPAL DISPLAY PANEL NDC 10094-210-60 Sympazan (clobazam) Oral film 10 mg Rx Only 60 Oral films PRINCIPAL DISPLAY PANEL NDC 10094-210-60 Sympazan (clobazam) Oral film 10 mg Rx Only 60 Oral films
PRINCIPAL DISPLAY PANEL NDC 10094-220-01 Sympazan (clobazam) Oral film 20 mg Rx Only 1 Oral films PRINCIPAL DISPLAY PANEL NDC 10094-220-01 Sympazan (clobazam) Oral film 20 mg Rx Only 1 Oral films
PRINCIPAL DISPLAY PANEL NDC 10094-220-60 Sympazan (clobazam) Oral film 20 mg Rx Only 60 Oral films PRINCIPAL DISPLAY PANEL NDC 10094-220-60 Sympazan (clobazam) Oral film 20 mg Rx Only 60 Oral films