Onfi Side Effects: What to Expect and When to Call Your Doctor

Onfi (clobazam) is an effective treatment for seizures associated with Lennox-Gastaut syndrome, but like all medications, it can cause side effects. Most side effects are mild and improve over time, but some can be serious and require immediate medical attention. This guide covers what to expect when starting Onfi, which side effects are most common, and the warning signs that mean you should call your doctor — or go to the emergency room.

Boxed Warning: Opioid Co-Use

Onfi carries a boxed warning — the FDA's most serious warning level — about the risks of combining it with opioid medications. Combining Onfi with opioids (such as codeine, morphine, oxycodone, or fentanyl) can cause profound sedation, slowed or stopped breathing (respiratory depression), coma, and death. If you are taking opioids for any reason, tell your prescriber before starting Onfi.

Common Side Effects of Onfi

The most frequently reported side effects in clinical studies of Onfi (occurring in at least 10% of patients more than placebo) include:

• Somnolence (sleepiness) or sedation: The most common side effect, especially in the first month of treatment. Generally diminishes with continued therapy as the body adjusts. Avoid driving or operating machinery until you know how Onfi affects you.
• Drooling (hypersalivation): More common in children and in patients taking higher doses.
• Constipation: A common benzodiazepine side effect; staying hydrated and eating fiber-rich foods can help.
• Lethargy and fatigue: Feelings of low energy and tiredness, often associated with the sedating effects of the medication.
• Fever (pyrexia): A reported side effect in clinical trials; tell your doctor if you develop a fever while starting Onfi, as it can also be an early sign of a serious skin reaction.
• Cough: Mild upper respiratory symptoms, including cough, have been reported.
• Slurred speech and coordination problems: Difficulty with balance, walking, and speech can occur, especially at higher doses.
• Behavioral changes: Irritability, agitation, or aggressive behavior have been reported, particularly in children. This is a known paradoxical reaction to some benzodiazepines.

Serious Side Effects That Require Immediate Medical Attention

These side effects are less common but serious. Seek emergency medical care immediately if you experience any of the following:

• Respiratory depression: Shallow or slowed breathing, especially when combined with opioids, alcohol, or other CNS depressants. Call 911 immediately if breathing stops or becomes severely compromised.
• Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN): Serious, potentially life-threatening skin reactions. Symptoms include painful red or purple blistering skin, peeling, rash, and sores in the mouth. Monitor closely for signs especially in the first 8 weeks of treatment. Stop Onfi at the first sign of any rash and call your doctor immediately.
• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms): The FDA issued a warning in December 2023 that clobazam can cause DRESS — a rare, life-threatening hypersensitivity reaction that starts as a rash but can rapidly progress to organ damage. Symptoms include fever, rash, swollen lymph nodes, and signs of organ injury. Seek emergency care immediately.
• Suicidal thoughts or actions: Like all anti-epileptic drugs, Onfi may increase the risk of suicidal thoughts or behaviors in a small number of patients — approximately 1 in 500. Call your doctor right away if you experience sudden changes in mood, feelings of hopelessness, or thoughts of self-harm.
• Withdrawal reactions: If Onfi is stopped suddenly, severe withdrawal symptoms can occur including seizures (potentially status epilepticus), hallucinations, shaking, muscle cramps, and extreme anxiety. Never stop Onfi without slowly tapering under your doctor's guidance.

Side Effects in Children vs. Adults

LGS begins in childhood, and Onfi is commonly used in pediatric patients. Children may experience the same side effects as adults, but behavioral changes — including increased aggression, irritability, or paradoxical hyperactivity — can be more prominent in children. Discuss any behavioral changes with your child's neurologist promptly.

Managing Common Side Effects

Most common side effects — especially sedation — improve after the first 4–8 weeks as your body adjusts. Some practical tips:

• Take the larger daily dose at bedtime to minimize daytime sedation
• Avoid alcohol completely — it increases clobazam's sedative effect by about 50%
• Maintain adequate hydration and fiber intake to manage constipation
• Don't drive or operate heavy machinery until you're sure how Onfi affects you

When to Call Your Doctor vs. When to Call 911

Call your doctor: new or worsening rash, behavioral changes, suicidal thoughts, persistent sedation that doesn't improve. Call 911 immediately: severe breathing difficulty, unresponsiveness, rapidly spreading rash with blistering or peeling skin, prolonged seizure (status epilepticus). For information on drug interactions that can increase side effect risk, see our guide on Onfi drug interactions.