CLOBAZAM: 10,596 Adverse Event Reports & Safety Profile

Table 4.

Description Proprietary

Name: ONFI ® Established Name: Clobazam Dosage Forms: Tablet and Oral Suspension Route of Administration: Oral Established Pharmacologic Class of Drug: Benzodiazepine Chemical Name: 7-Chloro-1-methyl-5-phenyl-1H-1,5 benzodiazepine-2,4( 3H,5H )-dione Structural Formula: Clobazam is a white or almost white, crystalline powder with a slightly bitter taste; is slightly soluble in water, sparingly soluble in ethanol, and freely soluble in methylene chloride. The melting range of clobazam is from 182ºC to 185ºC. The molecular formula is C 16 H 13 O 2 N 2 Cl and the molecular weight is 300.7. Each ONFI tablet contains 10 mg or 20 mg of clobazam. Tablets also contain as inactive ingredients: modified corn starch, lactose monohydrate, magnesium stearate, silicon dioxide, and talc. ONFI is also available for oral administration as an off-white suspension containing clobazam at a concentration of 2.5 mg/mL. Inactive ingredients include magnesium aluminum silicate, xanthan gum, citric acid monohydrate, disodium hydrogen phosphate dihydrate, simethicone emulsion, polysorbate 80, methylparaben, propylparaben, propylene glycol, sucralose, maltitol solution, berry flavor, purified water. onfi-01

AND USAGE Clobazam oral suspension is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. Clobazam oral suspension is a benzodiazepine indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. ( 1 )

AND ADMINISTRATION For doses above 5 mg/day administer in two divided doses ( 2.1 ) Patients ≤30 kg body weight: Initiate at 5 mg daily and titrate as tolerated up to 20 mg daily ( 2.1 ) Patients >30 kg body weight: Initiate at 10 mg daily and titrate as tolerated up to 40 mg daily ( 2.1 ) Dosage adjustment 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 ( 2.7 , 8.8 ) Tablets: Administer whole, broken in half along the score, or crush and mix in applesauce ( 2.3 ) Measure prescribed amount of oral suspension using provided adapter and dosing syringe ( 2.3 ) Tablets and Oral suspension: Can be taken with or without food ( 2.3 )

2.1 Dosing Information A daily dose of ONFI 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 weight group) has been shown to be effective, although effectiveness increases with increasing dose <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . 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 Body Weight >30 kg Body Weight Starting Dose 5 mg 10 mg Starting Day 7 10 mg 20 mg Starting Day 14 20 mg 40 mg

2.2 Discontinuation or Dosage Reduction of ONFI To reduce the risk of withdrawal reactions, increased seizure frequency, and status epilepticus, use a gradual taper to discontinue ONFI or reduce the dosage. Taper by decreasing the total daily dose 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.3 ) and Drug Abuse and Dependence ( 9.3 )]</span> .

2.3 Important Administration Instructions Instruct patients to read the &quot;Instructions for Use&quot; carefully for complete directions on how to properly dose and administer ONFI oral suspension.

Onfi

Tablet Oral Administration ONFI tablets can be taken with or without food. ONFI tablets can be administered whole, broken in half along the score, or crushed and mixed in applesauce.

Onfi

Oral Suspension Oral Administration ONFI oral suspension can be taken with or without food [see Clinical Pharmacology ( 12.3 )] . Shake ONFI Oral Suspension well before every administration. When administering the oral suspension, use only the oral dosing syringe provided with the product. Each carton includes two syringes, but only one syringe should be used for dosing. The second oral syringe is reserved as a replacement in case the first syringe is damaged or lost. Insert the provided adapter firmly into the neck of the bottle before first use and keep the adapter in place for the duration of the usage of the bottle. To withdraw the dose, insert the dosing syringe into the adapter and invert the bottle then slowly pull back the plunger to prescribed dose. After removing the syringe from the bottle adapter, slowly squirt ONFI Oral Suspension into the corner of the patient's mouth. Replace the cap after each use. The cap fits over the adapter when the adapter is properly placed. See ONFI Oral Suspension "Instructions for Use" for complete instruction on how to properly dose and administer the ONFI Oral Suspension.

2.4 Dosage Adjustments in Geriatric Patients Plasma concentrations at any given dose are generally higher in the elderly: proceed slowly with dose escalation. The starting dose should be 5 mg/day for all elderly patients. Then titrate elderly patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on weight) may be started on day 21 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 )]</span> .

2.5 Dosage Adjustments in CYP2C19 Poor Metabolizers In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam&apos;s active metabolite, will be increased. Therefore, in patients known to be CYP2C19 poor metabolizers, the starting dose should be 5 mg/day and dose titration should proceed slowly according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, an additional titration to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group) may be started on day 21 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.5 )]</span> .

2.6 Patients with Renal Impairment No dose adjustment is required for patients with mild and moderate renal impairment. There is no experience with ONFI in patients with severe renal impairment or end stage renal disease (ESRD). It is not known if clobazam or its active metabolite, N-desmethylclobazam, is dialyzable <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]</span> .

2.7 Dosage Adjustments in Patients with Hepatic Impairment ONFI is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of ONFI. For this reason, proceed slowly with dosing escalations. For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dose should be 5 mg/day in both weight groups. Then titrate patients according to weight, but to half the dose presented in Table 1, as tolerated. If necessary and based upon clinical response, start an additional titration on day 21 to the maximum dose (20 mg/day or 40 mg/day, depending on the weight group). There is inadequate information about metabolism of ONFI in patients with severe hepatic impairment. Therefore no dosing recommendation in those patients can be given <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.8 ), Clinical Pharmacology ( 12.3 )]</span> .

Clobazam oral suspension 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 , 5.7) ] . History of hypersensitivity to the drug or its ingredients ( 4 )

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.

6.1 Clinical 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) <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>.

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 Maximum daily dose of 10 mg for ≤30 kg body weight; 20 mg for >30 kg body weight c Maximum daily dose of 20 mg for ≤30 kg body weight; 40 mg for >30 kg body weight

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clobazam tablets. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.

Blood

Disorders: Anemia, eosinophilia, leukopenia, thrombocytopenia Eye Disorders: Diplopia, vision blurred Gastrointestinal Disorders: Abdominal distention General Disorders and Administration Site Conditions: Hypothermia Investigations: Hepatic enzyme increased Musculoskeletal: Muscle spasms Psychiatric Disorders: Agitation, anxiety, apathy, confusional state, depression, delirium, delusion, hallucination Renal and Urinary Disorders: Urinary retention Respiratory Disorders: Aspiration, respiratory depression Skin and Subcutaneous Tissue Disorders: Rash, urticaria, angioedema, and facial and lip edema

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 clobazam oral suspension 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: Clobazam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal ( 5.9 , 8.1 )

5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including clobazam oral suspension, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe clobazam oral suspension 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 clobazam oral suspension is used with opioids <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including clobazam oral suspension, 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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence ( 9.2 )]</span>. Before prescribing clobazam oral suspension and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of clobazam oral suspension, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clobazam oral suspension 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.

5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clobazam oral suspension or reduce the dosage <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>. 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 clobazam oral suspension, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of clobazam oral suspension 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 [see Drug Abuse and Dependence ( 9.3 )].

5.4 Potentiation of Sedation from Concomitant Use with Central Nervous System Depressants Since clobazam oral suspension has a central nervous system (CNS) depressant effect, patients or their caregivers should be cautioned against simultaneous use with other CNS depressant drugs or alcohol, and cautioned that the effects of other CNS depressant drugs or alcohol may be potentiated <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.5 Somnolence or Sedation Clobazam oral suspension causes somnolence and sedation. In clinical trials, somnolence or sedation was reported at all effective doses and was dose-related. In general, somnolence and sedation begin within the first month of treatment and may diminish with continued treatment. Prescribers should monitor patients for somnolence and sedation, particularly with concomitant use of other central nervous system depressants. Prescribers should caution patients against engaging in hazardous activities requiring mental alertness, such as operating dangerous machinery or motor vehicles, until the effect of clobazam oral suspension is known.

5.6 Serious Dermatological Reactions Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam oral suspension in both children and adults during the postmarketing period. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment initiation or when re-introducing therapy. Clobazam oral suspension should be discontinued at the first sign of rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

5.7 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including clobazam oral suspension. These events can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Clobazam oral suspension should be discontinued if an alternative etiology for the signs or symptoms cannot be established <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

5.8 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including clobazam oral suspension, 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% confidence interval [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 to 100 years) in the clinical trials analyzed.

Table

2 shows absolute and relative risk by indication for all evaluated AEDs.

Table

2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 Patients Relative Risk: Incidence of Drug Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 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 clobazam oral suspension or any other AED must balance the risk of suicidal thoughts or behavior 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. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

5.9 Neonatal Sedation and Withdrawal Syndrome Use of clobazam 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>. Monitor neonates exposed to clobazam during pregnancy or labor for signs of sedation and monitor neonates exposed to clobazam during pregnancy for signs of withdrawal; manage these neonates accordingly.

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 )

7.1 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span>.

7.2 CNS Depressants and Alcohol Concomitant use of SYMPAZAN ® with other CNS depressants may increase the risk of sedation and somnolence <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>. Alcohol, as a CNS depressant, will interact with SYMPAZAN ® in a similar way and also increases clobazam&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>.

7.3 Effect 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 ® <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) , Patient Counseling Information (17) ]</span>.

Drugs

Metabolized by CYP2D6 SYMPAZAN ® inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary [see Clinical Pharmacology (12.3) ].

7.4 Effect 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) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. 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.