Clobazam

Clobazam is a medication that belongs to the benzodiazepine class. It’s primarily used to treat seizures, specifically in treating epileptic disorders. Benzodiazepines like clobazam affect the central nervous system and enhance the activity of a neurotransmitter called gamma-aminobutyric acid (GABA). This, in turn, helps to reduce abnormal electrical activity in the brain, which can contribute to seizures.

It’s important to note that clobazam should be used under the guidance of a healthcare professional, as it can have potential side effects and interactions with other medications. If you or someone you know is prescribed clobazam, it’s crucial to follow the prescribed dosage and consult a healthcare provider about any concerns or questions you may have.

Pharmacokinetics

Clobazam is well absorbed from the gastrointestinal tract, and peak plasma concentrations are reached 1 to 4 hours after oral doses. It is about 85% bound to plasma proteins. Clobazam is highly lipophilic and rapidly crosses the blood-brain barrier. It is metabolized in the liver by demethylation and hydroxylation but unlike the 1,4-benzodiazepines such as diazepam, clobazam, a 1,5-benzodiazepine, ishydroxylatedatthe4-position rather than the 3-position. Clobazam is excreted unchanged and as metabolites mainly in the urine. 

Uses and Administration

Clobazam is a long-acting 1,5-benzodiazepine with uses similar to diazepam (a 1,4-benzodiazepine). It may be used as an adjunct in treating epilepsy with other antiepileptics, although the development of tolerance or sedation may limit its use. It is also used in the short-term treatment of acute anxiety. As an adjunct in epilepsy, usual oral doses in the UK are 20 to 30 mg daily, increased if necessary to a maximum of 60 mg daily. For doses in children, see below. As with other antiepileptics, withdrawal of clobazam therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures. 

For the short-term management of acute anxiety, oral doses of 10 to 30 mg daily may be taken in divided doses or as a single dose at night; up to 80 mg daily has been used in hospitalized patients with severe anxiety states. Low initial doses and cautious increments to a usual daily dose of 10 to 20 mg are recommended in elderly or debilitated patients.

Administration in Children

In the UK, clobazam is licensed for use as an adjunct in epilepsy in children over three years of age; no more than half the adult dose should be given. Alternatively, the BNFC suggests the following oral doses according to age:

• 1 month to 12 years: initially 125 micrograms/kg twice daily, increased every 5 days to a usual maintenance dose of 250 micrograms/kg twice daily. The maximum dose is 500 micrograms/kg twice daily and should not exceed 15 mg twice daily.
• 12 to 18 years: initially 10 mg twice daily, increased every 5 days to a maintenance dose of 10 to 15 mg twice daily. The dose should not exceed 30 mg twice daily

The BNFC also suggests that clobazam may be given for cluster seizures and as monotherapy under specialist supervision for catamenial seizures (usually for 7 to 10 days each month, just before and during menstruation).

Epilepsy

Benzodiazepines are sometimes used to manage epilepsy, but problems of sedation, dependence, and tolerance to the antiepileptic effects limit their long-term use.

Clobazam, a 1,5-benzodiazepine, is considered to be better tolerated than conventional benzodiazepines and has been widely used for adjunctive oral therapy in patients with epilepsy. Clobazam is active against partial and generalized seizures in epilepsy of widely differing etiology in patients of all ages. It has also been used for short-term cover in patients with intermittent seizures, including in women with catamenial epilepsy (seizures associated with menstruation) or patients whose epileptic attacks occur in clusters.

Clobazam has also been tried with some success in children, including those with refractory epilepsy and epileptic encephalopathy. However, a recent systematic review concluded that although clobazam may reduce seizure frequency and be most effective in partial-onset seizures, it was unclear who would best benefit from its use and over what time frame.

Neuropathic Pain

There has been a mention of the complete relief of phantom limb pain refractory to other therapy in an elderly patient given clobazam 10 mg three times daily.

Dependence and Withdrawal

Like other benzodiazepines, clobazam has the potential for dependence and withdrawal symptoms, especially if used for an extended period or in higher doses than prescribed. Dependence means that the body becomes accustomed to the presence of the medication, and abrupt discontinuation can lead to withdrawal symptoms.

Withdrawal symptoms may include anxiety, insomnia, irritability, tremors, sweating, and, in severe cases, seizures. Taking clobazam precisely as prescribed by a healthcare professional is crucial to minimize the risk of dependence and withdrawal. Abruptly stopping the medication or making significant changes to the dosage without medical guidance can increase the likelihood of withdrawal symptoms.

If there is a need to stop or adjust the medication, it should be done under the supervision of a healthcare provider, who may gradually taper the dosage to minimize withdrawal effects.

It’s also crucial for individuals to communicate openly with their healthcare providers about any concerns or side effects they may be experiencing. This allows for a collaborative approach to managing the condition while minimizing potential risks associated with the medication.

Adverse Effects

Clobazam, like other medications, can cause various adverse effects. Common side effects may include drowsiness, dizziness, constipation, and headache. These effects are usually temporary and may subside as the body adjusts to the medication.

However, some more serious adverse effects may occur, and it’s essential to seek medical attention if any of these occur:

1. Allergic Reactions: Symptoms may include rash, itching, swelling, severe dizziness, or difficulty breathing. Allergic reactions are rare but can be severe.
2. Mood Changes: Some individuals may experience changes in mood or behavior, including increased irritability, aggression, or suicidal thoughts. It’s essential to report any significant changes to a healthcare provider.
3. Severe Drowsiness or Weakness: Clobazam can cause extreme drowsiness or weakness, impairing cognitive and motor skills. Activities requiring alertness, such as driving, should be approached with caution.
4. Respiratory Depression: In rare cases, benzodiazepines, including clobazam, can suppress respiratory function, especially when taken in high doses or combined with other substances that depress the central nervous system.
5. Dependence and Withdrawal: As mentioned earlier, long-term use of clobazam can lead to dependence and withdrawal symptoms if the medication is abruptly stopped.

It’s crucial to inform a healthcare provider about any side effects experienced while taking clobazam. They can help assess the risks and benefits of continued use and make any necessary adjustments to the treatment plan.

Breastfeeding

Benzodiazepines, such as clobazam, given to the mother may cause neonatal sedation, and breastfeeding should be avoided. 

Effects on Menstruation

Occasionally, the use of clobazam before menstruation for catamenial epilepsy appeared to delay the periods.

Effects on the Skin

Report of toxic epidermal necrolysis developed in light-exposed areas in a patient treated with clobazam.

Porphyria

Clobazam is considered unsafe in patients with porphyria, although there is conflicting evidence of porphyrinogenicity.

Precautions

When taking clobazam, it’s essential to follow certain precautions to ensure the safe and effective use of the medication. Here are some key precautions:

1. Medical History: Inform your healthcare provider about your complete medical history, especially if you have a history of drug or alcohol abuse, liver disease, kidney disease, lung/breathing problems, or a personal or family history of a substance use disorder.
2. Pregnancy and Breastfeeding: Clobazam may harm an unborn baby, so discussing the risks and benefits with your healthcare provider if you are pregnant or planning to become pregnant is essential. Additionally, clobazam can pass into breast milk, so breastfeeding while taking this medication should be discussed with a healthcare professional.
3. Drug Interactions: Inform your healthcare provider about all medications, vitamins, and supplements you currently take, as clobazam can interact with other drugs. Combining clobazam with certain medications may increase the risk of side effects or affect the drug’s effectiveness.
4. Alcohol and Other Substances: Avoid alcohol and recreational drugs while taking clobazam, as they can enhance the medication’s sedative effects and increase the risk of side effects.
5. Driving and Operating Machinery: Clobazam can cause drowsiness and dizziness. Avoid driving or operating heavy machinery until you know how the medication affects you.
6. Regular Monitoring: Regularly attend follow-up appointments with your healthcare provider to monitor and adjust your treatment plan if needed.
7. Dosage Changes: Do not change the dosage or stop taking clobazam without consulting your healthcare provider. Abruptly stopping the medication can lead to withdrawal symptoms.

Always consult your healthcare provider for personalized advice based on your specific health condition and needs.

Interactions

Clobazam can interact with various medications, potentially affecting their effectiveness or increasing the risk of side effects. It’s crucial to inform your healthcare provider about all your medications, supplements, and over-the-counter drugs to ensure a comprehensive understanding of potential interactions. Here are some notable interactions:

1. Central Nervous System Depressants: Clobazam has sedative effects, and combining it with other medications or substances that depress the central nervous system, such as alcohol, other benzodiazepines, opioids, or muscle relaxants, can enhance sedation and increase the risk of respiratory depression.
2. Antiepileptic Drugs (AEDs): Clobazam is often prescribed as an adjunctive treatment for epilepsy. It’s important to discuss potential interactions with other antiepileptic drugs to ensure proper management and minimize the risk of side effects.
3. Strong CYP2D6 Inhibitors: Clobazam is metabolized by the liver, and drugs that inhibit the CYP2D6 enzyme may affect its metabolism. Drugs like fluoxetine and paroxetine, which are strong CYP2D6 inhibitors, may increase clobazam levels.
4. CYP3A4 Inducers and Inhibitors: Clobazam is also metabolized by the CYP3A4 enzyme. Medications that induce or inhibit CYP3A4 may influence clobazam levels. Examples include rifampin (an inducer) and ketoconazole (an inhibitor).
5. Oral Contraceptives: Clobazam may decrease the effectiveness of hormonal contraceptives. It’s important to discuss alternative contraceptive methods with your healthcare provider if you are taking clobazam and using hormonal contraceptives.
6. Grapefruit Juice: Grapefruit juice can inhibit the metabolism of clobazam, potentially increasing its levels in the blood. It’s advisable to avoid consuming grapefruit or grapefruit juice while taking clobazam.

This list is not exhaustive, and individual responses to medications can vary. Always consult your healthcare provider to ensure that the benefits of clobazam outweigh potential risks and to receive personalized advice based on your medical history and current medications.

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

Synonyms: Clobazamum; H-4723; HR-376; Klobatsaami; Klobazam; Klobazamas; LM-2717

BAN: Clobazam

USAN: Clobazam

INN: Clobazam [rINN (en)]

INN: Clobazam [rINN (es)]

INN: Clobazam [rINN (fr)]

INN: Clobazamum [rINN (la)]

INN: Клобазам [rINN (ru)]

Chemical name: 7-Chloro-1,5-dihydro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione

Molecular formula: C16H13ClN2O2 =300.7

CAS: 22316-47-8

ATC code: N05BA09

Read code: y00Jo [Epilepsy Only]; y01yi

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Clobazam). A white or almost white crystalline powder. Slightly soluble in water, sparingly soluble in alcohol, and freely soluble in dichloromethane.