Sympazan (clobazam) Seizure Medication Side Effects & Warnings


Generic drug: clobazam

Brand name: Sympazan

What is Sympazan (clobazam), and how does it work?

Sympazan is a prescription medicine used along with other medicines to treat seizures associated with Lennox-Gastaut Syndrome in people 2 years of age or older.

It is not known if Sympazan is safe and effective in children less than 2 years old.

What are the side effects of Sympazan?

WARNING

RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.

  • Reserve concomitant prescribing of these drugs for use 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

The most common side effects of Sympazan  include:

These are not all the possible side effects of Sympazan. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What is the dosage for Sympazan?

Dosing 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. 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

Discontinuation 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.

Important 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. 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.

Dosage Adjustments In Geriatric Patients

  • Plasma concentrations at any given dose are generally higher in geriatric patients.
  • 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.

Dosage Adjustments In CYP2C19 Poor Metabolizers

  • In CYP2C19 poor metabolizers, levels of N-desmethylclobazam, clobazam's active metabolite, will be increased.
  • 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.

Dosage Adjustments In Patients With Hepatic Impairment

  • Sympazan is hepatically metabolized; however, there are limited data to characterize the effect of hepatic impairment on the pharmacokinetics of Sympazan.
  • For patients with mild to moderate hepatic impairment (Child-Pugh score 5-9), the starting dosage should be 5 mg/day (regardless of weight).
  • Then proceed slowly with dosing escalations; titrate patients 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.
  • There is inadequate information about metabolism of clobazam in patients with severe hepatic impairment. Therefore, no dosing recommendation can be given for those patients.

What drugs interact with Sympazan?

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 GABAA sites, and opioids interact primarily at mu receptors.
  • When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.
  • Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

CNS Depressants And Alcohol

  • Concomitant use of Sympazan  with other CNS depressants may increase the risk of sedation and somnolence.
  • 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.

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.
Drugs Metabolized By CYP2D6
  • Sympazan inhibits CYP2D6. Dose adjustment of drugs metabolized by CYP2D6 may be necessary.

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 Ndesmethylclobazam, 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).
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.
  • Consider a reduction in dosage of cannabidiol or clobazam if adverse reactions known to occur with Sympazan are experienced.

Does Sympazan cause addiction or withdrawal symptoms?

Drug Abuse And Dependence

Controlled Substance
  • Sympazan contains clobazam, a Schedule IV controlled substance.
Abuse
Dependence

Physical Dependence

Acute Withdrawal Signs and Symptoms

Protracted Withdrawal Syndrome

Tolerance

  • 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.
  • The following adverse reactions have occurred with benzodiazepine abuse and/or misuse:
  • The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse:
  • 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.
    • 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.
    • To reduce the risk of withdrawal reactions, use a gradual taper to discontinue Sympazan or reduce the dosage.
    • Acute withdrawal signs and symptoms associated with benzodiazepines have included
    • More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included
    • Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal.
    • Protracted withdrawal symptoms may last weeks to more than 12 months.
    • As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.
    • Tolerance to Sympazan may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).
    • Tolerance to the therapeutic effect of Sympazan may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

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Is Sympazan safe to use while pregnant or breastfeeding?

  • There are no adequate and well-controlled studies of Sympazan in pregnant women.
  • Available data suggest that the class of benzodiazepines is not associated with marked increases in risk for congenital anomalies.
  • Although some early epidemiological studies suggested a relationship between benzodiazepine drug use in pregnancy and congenital anomalies such as cleft lip and/or palate, these studies had considerable limitations.
  • More recently completed studies of benzodiazepine use in pregnancy have not consistently documented elevated risks for specific congenital anomalies.
  • There is insufficient evidence to assess the effect of benzodiazepine pregnancy exposure on neurodevelopment.
  • There are clinical considerations regarding exposure to benzodiazepines during the second and third trimester of pregnancy or immediately prior to or during childbirth.
  • These risks include decreased fetal movement and/or fetal heart rate variability, “floppy infant syndrome,” dependence, and withdrawal.
  • Sympazan should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
  • Sympazan is excreted in human milk. Postmarketing experience suggests that breastfed infants of mothers taking benzodiazepines, such as Sympazan, may have effects of lethargy, somnolence and poor sucking.
  • The effect of Sympazan on milk production is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Sympazan and any potential adverse effects on the breastfed infant from Sympazan or from the underlying maternal condition.
  • If exposing a breastfed infant to Sympazan, observe for any potential adverse effects.

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