Clobazam

Clobazam is a benzodiazepine which belongs to the same family of drugs that includes lorazepam (Ativan) ,diazepam (Valium), midazolam (Versed) and clonazepam (Klonopin). Clobazam is different from the other benzodiazepines because it is utilized for the long-term treatment of epilepsy due to its effectiveness and relatively low tendency to produce sedation.

Onfi
Tablet
Onfi 10mg tablet

10 mg with a functional score for oral administration.

Each ONFI tablet is a white to off-white, oval tablet with a functional score on one side and a “1” and “0” debossed on the other side.

Onfi 20mg tablet

20 mg with a functional score for oral administration.

Each ONFI tablet is a white to off-white, oval tablet with a functional score on one side and a “2” and “0” debossed on the other side.

Liquid Solution
Onfi Oral Solution

2.5 mg/mL for oral administration. Each bottle contains 120 mL of an off-white suspension.

Sympazan

Indications

Clobazam belongs to a class of medications called benzodiazepines (BEN-zo-di-AZ-ah-peens). The medication is indicated for use in patients as an add- on medication for seizures associated with Lennox-Gastaut syndrome. Patients must be 2 years of age or older.

Forms

Onfi is available in a number of dose sizes.  It should be started slowly in a divided dose twice daily, and it should be done according to body weight. Serum levels of clobazam and its metabolites require 5-9 days to reach a steady state level. Onfi, produced by Lundbeck, is available in the United States as 10 mg and 20 mg scored tablets, as well as 2.5 mg/mL oral suspension.

Dosing

The dose of Onfi depends on patient's weight.  The total daily dose should be divided into 2 daily doses.

For patients at or less than 30 kilograms of body weight, start Onfi at 5 milligrams daily and slowly increase the medication up to 20 milligrams a day as tolerated by the patient.

For patients more than 30 kilograms of body weight, start Onfi at 10 milligrams daily and increase the dose up to 40 milligrams a day as tolerated by the patient.

You need to adjust the dose in older patients, patients who are known to slowly metabolize medications through the liver (known CYP2C19 metabolizers) and individuals with liver disease or problems.

How to take and store Clobazam?

Clobazam tablets should be swallowed whole, followed by at least a half a glass of water.

It's OK to take clobazam either with food or without food. To give it to small children or others who cannot swallow tablets, you can crush it and mix it with a spoonful of soft food such as applesauce, yogurt, or ice cream or use the suspension. 

Store the tablets at room temperature in a dry place that is out of the reach of children.

Using the Oral Suspension:

 Shake the bottle well right before you take each dose.  

Measure your dose of Onfi oral suspension using the bottle adapter and dosing syringes that are given with the suspension. 

Use Onfi oral suspension within 90 days of first opening the bottle.  Throw away any unused Onfi suspension after this time.

Missed Doses

In general, a forgotten dose should be taken right away. If it is almost time for the next dose, just take one dose, not a double dose, and call the doctor's office for more advice.

Do your best to follow the doctor's directions. If you forget doses often, it may be a good idea to get a special pillbox or watch with an alarm to remind you.

Taking the right amount of seizure medicine on time every single day is the most important step in preventing seizures! 

Mechanisms of actions of Clobazam

The mechanism of action for clobazam is not fully understood but is thought to involve what is known as potentiation of GABAergic neurotransmission resulting from binding at a benzodiazepine site at the GABA(A) receptor.

Clinical Pharmacology of Clobazam

- The peak plasma level or the level of the drug in the blood is dose proportional over the dose range of 10-80 mg.

- Clobazam is broken down to a metabolite known as N-desmethylclobazam, which has about a fifth the activity of clobazam.  

- The mean half-life or the amount of time that the drug spends in the system as well as for the main metabolite is 36-42 hours for clobazam itself and 71-82 hours for its main metabolite.  

- The drug is rapidly absorbed after oral administration and it peaks in 30 minutes to 4 hours after single or multiple-dose administration.  It is bioavailable.  Food does not affect absorption.  It can be easily crushed in items such as apple sauce or other foods. 

- Clobazam is lipophilic and distributes rapidly throughout the body.  It has a protein binding of 80-90% for clobazam and 70% for its main metabolites.

- Clobazam is metabolized in the liver.  The major metabolic pathway does involve CYP3A4, and to a lesser extent, CYP2C19 and CYP2B6 isoenzymes.  The main metabolite of the drug is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations of this can be 3 times higher than its parent compound.  Eleven percent of the drug is excreted in feces and 82% is in the urine.

- There is no apparent difference in the metabolism of clobazam between women and men. 

- There is no significant effect of race on the clearance of clobazam either. 

- Renal impairment has been evaluated and patients with severe renal impairment have not been studied extensively, but it apparently seems to be non-problematic in patients with mild or moderate renal impairment. 

- In liver problems, there is limited data to address how things get affected with this condition; however, one needs to exercise caution with regards to its use in this situation.  There is no specific recommendation from the company as to what should be done with people who have kidney or renal problems.

Efficacy of Clobazam

Clobazam is being marketed in the United States under the trade name of Onfi.  The FDA indication for clobazam is strictly for add-on therapy for treatment of seizures associated with Lennox-Gastaut syndrome in children from age 2 and older. 

- The effectiveness for this drug was established in 2 multi-center control studies done specifically to bring the drug to the U.S. market.  Both studies were similar in terms of the patient populations that were studied.  The first study was a randomized, double-blind, placebo-controlled study that looked at patients who were aged 2 to 54 years with a current or prior diagnosis of Lennox-Gastaut syndrome.  The patients were divided into 2 groups by weight, those who were less than 30 kg and those who were greater than 30 kg, and then they were randomized to 1 of 3 maintenance doses of the medication ( 5 mg- Low, 10 mg Medium and 20 mg High doses).  The primary measure for the study was the percent seizure reduction and weekly frequency of various seizures that typify the syndrome, primarily drop, tonic, or myoclonic seizures over a 4-week baseline to a 12-week period of observation on the medication.

In the low-dose group, there was a 41.2% reduction of total seizures.  In the medium-dose group, there was a 49.4% reduction in seizures, and in the high-dose group, a 68.3% reduction.  The placebo group showed only a 12.1% reduction.  Because this is a drug in the benzodiazepine family, they also looked at the issue of tolerance which is common to this drug group.  Tolerance is defined as whether a drug maintains its effectiveness over time at a given dose. In other benzodiazepines, one often needs to take more of a given drug in order to maintain effectiveness.  There was no significant development of tolerance over a 3-month period of observation.

- In the second major study, also a randomized double-blind comparison study of high- and low-dose Onfi consisting of patients aged 2-25 years with a current or prior diagnosis of Lennox-Gastaut, divided into 2 weight groups and then randomized to either a low target dose of 5 mg or 10 mg depending on whether they weighed more or less than 30 kg.  In the high dose group, the target daily dose of 20 mg for less than 30 kg body weight vs. 40 mg for more than a 30 kg body weight. Results showed a significant reduction in seizure frequency in the high dose compared to the low dose group with a median percent seizure reduction of 93% vs. 29%.  Based on these analyses, the drug was approved.

- In other studies done outside of the US, clobazam has been found to be effective amongst almost all seizure types. However, excitement over these findings has been tempered by the fact that the benefits can often be short-lived.  In one large Canadian clobazam cooperative study, more than 40% of patients with a single seizure type had a 50% or greater reduction in seizure frequency and 60% of patients with multiple seizure types had improvement in at least one type of seizures; however, side effects did occur  with the most common being drowsiness.

Common side effects of Clobazam

The most commonly reported side effect with this drug includes tiredness and sedation. In general, these tend to be dose related with the higher doses resulting in higher reports of adverse effects. 

One needs to be careful about the use of this drug with other depressant drugs or alcohol. 

Because it is a benzodiazepine, abrupt discontinuation should be avoided. This drug needs to be tapered slowly, otherwise withdrawal symptoms can occur. Withdrawal symptoms may include convulsions, hallucinations, behavioral disorder, tremor and anxiety. There is the chance of physical and psychological dependence on this drug. 

Similar to other seizure drugs, there is also the risk of suicidal thought or behaviors in patients who take this drug. 

The most common side effects that led to treatment stoppage in the control trials included lethargy, somnolence, ataxia, aggression, fatigue and insomnia.

Other common side effects include gastrointestinal issues, decreased appetite and issues related to depression or psychiatric problems such as aggression or insomnia.

Serious Side effects of Clobazam

Most people who take clobazam have no side effects or mild side effects that go away in a short time with no lasting harm. Serious reactions, such as a drug-related skin rash, have been extremely rare. Call your doctor right away if you notice a rash soon after you start taking clobazam.

Like many other seizure medicines, clobazam makes some people feel sleepy or uncoordinated. If you've just started taking clobazam or have just had your dosage increased, be careful when doing things that could be dangerous until you know how it will affect you. Be especially cautious if you tend to be sensitive to medications or if you are taking another medicine that could make you sleepy.

One of the great dangers in using medications like clobazam is the tendency to increase the dose as tolerance develops. To a certain extent, this is necessary, but adverse effects may be increased more than seizure control. If the dosage is increased gradually over a long period, subtle changes in personality (such as irritability, depression, or decreased motivation) or problems such as impaired memory may go unnoticed or be considered natural for that person.

High doses sometimes are prescribed for children and adults, especially those with developmental disabilities. Problems with thinking and behavior may be the result. If the dose has been increased gradually over many months or years, it can be hard to separate the effects of the clobazam (or other benzodiazepines) from the effects of other medications, seizures, and other neurological and psychological disorders.

An important concern when people with epilepsy take clobazam or other benzodiazepines is the risk that seizures will become more frequent or more severe if the medicine is reduced or stopped. Withdrawal syndrome usually begins as soon as the patient stops taking the medicine and lasts for 8 to 10 days. The longer the person has been taking clobazam and the higher the dose, the greater the tolerance and therefore the higher the risk of worsening seizure control. Even small, gradual dose reductions can temporarily increase seizure activity, but the long-term decrease in effects like drowsiness and depression often makes the change worthwhile.

Besides increased seizure activity, other symptoms of withdrawal include:

  • drowsiness
  • dizziness
  • poor coordination
  • drooling
  • restlessness or aggressiveness

Tell your doctor if you notice these symptoms when your dosage is being reduced.

On July 10, 2008, an advisory panel was convened by the Food and Drug Administration (FDA) to review data that the FDA had previously collected from drug studies showing an association between many of the antiepileptic drugs (AEDs) and suicidal ideation and behavior, which together are called suicidality. According to the FDA’s Alert, among the patients with epilepsy in these drug studies, 1 out of 1000 people taking the placebo (inactive substance) showed suicidality compared to approximately 3.5 out of 1000 people who took an AED. The FDA advisory panel voted to accept the FDA's data at its meeting on July 10.

Taking antiepileptic medicines may increase the risk of having suicidal thoughts or actions;

  • Do not make any changes to the medication regimen without first talking with the responsible healthcare professional;
  • Pay close attention to any day-to-day changes in mood, behavior and actions. These changes can happen very quickly so it is important to be mindful of any sudden differences.

Be aware of common warning signs that might be a signal for risk of suicide. Some of these are:

  • Talking or thinking about wanting to hurt yourself or end your life
  • Withdrawing from friends and family
  • Becoming depressed or having your depression get worse
  • Becoming preoccupied with death and dying
  • Giving away prized possessions

We again urge patients and families to contact their doctor before stopping an epilepsy medication because this may possibly lead to seizures and worsening of mood.

Impact of Clobazam on bone health

See package insert.

Other Uses of Clobazam

Some evidence suggests efficacy against photosensitive epilepsy and myoclonic seizures.

Clobazam Contraindications

See package insert.

Clobazam Interactions with other medications

See package insert.

Clobazam effects on Children

See package insert.

Clobazam and Pregnancy

Onfi or clobazam is a pregnancy Category C drug.  There are no adequate or well controlled studies of Onfi in pregnant women and no adequate developmental toxicity studies of clobazam in animals.  Onfi is excreted in human milk.  The effects of this exposure on infants are unknown.  The drug has not been utilized in children under the age of 2 and therefore caution is needed with addressing this group of individuals.

Clobazam effects on Seniors

See package insert.

Clobazam Dosing and titration

Onfi is available in a number of dose sizes.  It should be started slowly in a divided dose twice daily, and it should be done according to body weight.  Serum levels of clobazam and its metabolites require 5-9 days to reach a steady state level. Clobazam will be available in the United States as a 5 mg, 10 mg and 20 mg tablet for oral administration.  The highest dose was 20 mg for less than 30 kg body weight and 40 mg for greater than 30 kg body weight.

Special Concerns for Clobazam

See package insert.

Clobazam Package insert

In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine.

You can also read these documents (also called "prescribing information") online. The U.S. package insert for ONFI (clobazam) is found at:

https://www.lundbeck.com/upload/us/files/pdf/Products/Onfi_PI_US_EN.pdf

Clobazam References for Professionals

Abstracts of articles relevant to this topic are available through http://www.ncbi.nlm.nih.gov/pubmed a service of the National Library of Medicine:

Here are links to some articles relevant to this subject:

Conry JA, Ng YT, Paolicchi JM, et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia 2009; 50:1158.
 
Ng YT, Conry JA, Drummond R, et al. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology 2011; 77:1473.

Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group. Epilepsia 2000 Sep;41(9):1179-86. PMID: 10999557.

Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. European Levetiracetam Study Group. Epilepsia 2000 Oct;41(10):1276-83. PMID: 11051122.

Cramer JA, Ben Menachem E, French J. Review of treatment options for refractory epilepsy: new medications and vagal nerve stimulation. Epilepsy Res 2001 Nov;47(1-2):17-25. PMID: 11673017.

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