The FDA approved Lundbeck, Inc's Onfi (clobazam) as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients that are 2 years and older.
Lundbeck, Inc’s Onfi
Monica Holmberg, PharmD, BCPS | April 26, 2012
The FDA has approved Lundbeck, Inc’s Onfi (clobazam) as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years and older.1
Patients with LGS often experience a wide variety of frequent seizures, including atonic, tonic, and myoclonic seizures, which may cause falls and injuries. LGS is usually diagnosed before 4 years of age and often continues into adulthood.2,3
Onfi will be available as 5-, 10-, and 20-mg tablets.1
PHARMACOLOGY AND PHARMACOKINETICS
Onfi is a 1,5-benzodiazepine whose exact mechanism of action is not understood. It is believed to involve potentiation of GABAergic neurotransmission as a result of binding at the benzodiazepine site of the GABAA
Onfi undergoes extensive hepatic metabolism and is converted to an active metabolite, N-desmethylclobazam. Although the metabolite has about onefifth the activity of its parent compound, it has a longer elimination half-life (36 to 42 hours for Onfi vs 71 to 82 hours for N-desmethylclobazam) and has 3 to 5 times the plasma concentration of Onfi at therapeutic doses.
The clearance of Onfi was decreased in elderly patients and should be dosed accordingly. Gender and race did not affect the pharmacokinetics of Onfi.1
DOSAGE AND ADMINISTRATION
Onfi is dosed by weight per the following titration, with doses over 5 mg per day given as 2 divided doses:
• Patients weighing 30 kg or less:
-Starting daily dose: 5 mg
-Day 7: 10 mg
-Day 14: 20 mg
• Patients weighing more than 30 kg:
-Starting daily dose: 10 mg
-Day 7: 20 mg
-Day 14: 40 mg
Onfi can be taken with or without food. The tablets can be swallowed whole or crushed and mixed in applesauce. Dose reductions or discontinuation should be made gradually. Dose adjustments are required in geriatric patients, patients who are known to be poor metabolizers of cytochrome P450 (CYP) 2C19, or patients with mild or moderate hepatic impairment. There is insufficient information available to determine the dose of Onfi in patients with severe hepatic impairment. 1
Onfi was evaluated in 2 multicenter, randomized, double-blind controlled trials to determine if the addition of Onfi to existing antiepileptic medications would reduce the weekly frequency of atonic, tonic, or myoclonic seizures (“drop seizures”) in patients older than 2 years.
In study 1, patients were randomized to receive either placebo, low-dose Onfi, medium-dose Onfi, or high-dose Onfi. All doses of Onfi were superior to placebo at reducing drop seizures, and the highest dose appeared to be most effective.
Study 2 compared high-dose Onfi with low-dose Onfi and found the higher dose to be more effective.1,3
CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS
There are no contraindications to treatment with Onfi.
Onfi may cause somnolence or sedation; this effect may be increased with concurrent use of other central nervous system depressants. Rapid dose reduction or discontinuation may result in withdrawal. Onfi is a Schedule IV medication. Patients with a history of substance abuse should be monitored for signs of dependence.
Antiepileptic medications such as Onfi may increase the risk of suicidal thoughts or behavior. Patients using Onfi should be monitored for changes in thoughts or behavior. Onfi is a Pregnancy Category C.1
It is excreted into human breastmilk and should not be used during breast-feeding.1,2
Onfi should not be used in patients younger than 2 years.
Onfi may decrease the efficacy of oral contraceptives. Some medications that are metabolized by CYP2D6 may require lower doses when used with Onfi. A lower dose of Onfi may be necessary when it is used with strong or moderate CYP2C19 inhibitors. Alcohol increases Onfi’s plasma concentration by about 50%.
Side effects (frequency >5%) during treatment with Onfi included somnolence or sedation, drooling, constipation, cough, urinary tract infection, aggression, insomnia, dysarthria, and fatigue.
Onfi will be dispensed with a Medication Guide for patients and caregivers.1 SPT
1. Onfi complete prescribing information. www.lundbeck.com/upload/us/files/pdf/Products/Onfi_PI_US_EN.pdf. Accessed March 2012.
2. ONFI (clobazam) tablets now available in the U.S. at retail pharmacies. www.onfi.com/local/pdf/Onfi_NowAvailable.pdf. Accessed March 2012.
3. FDA approves Onfi to treat severe type of seizures. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm276932.htm. Accessed March 2012.
About the Author
Monica Holmberg, PharmD, BCPS, resides in Phoenix, Arizona.