Clorazepate Drug Interactions You Need to Know About

Clorazepate (Tranxene) is a benzodiazepine that interacts with a long list of medications, supplements, and substances—some of which can be life-threatening. The FDA has issued a boxed warning specifically about the danger of combining Clorazepate with opioids.

Whether you're starting Clorazepate for the first time or adding a new medication to your routine, this guide covers the interactions you need to know about and what to discuss with your doctor.

How Drug Interactions Work With Clorazepate

Clorazepate is converted in your stomach to its active metabolite, nordiazepam, which works by enhancing GABA—your brain's calming neurotransmitter. Most of Clorazepate's interactions fall into two categories:

1. Additive CNS depression — Other medications that slow down brain activity can stack on top of Clorazepate's effects, causing dangerous levels of sedation, respiratory depression, or even death.
2. Metabolic interactions — Medications that affect liver enzymes (specifically CYP enzymes) can increase or decrease nordiazepam levels in your blood, making Clorazepate either too strong or not effective enough.

Major Drug Interactions (Potentially Life-Threatening)

These combinations carry serious risks and require careful medical supervision or should be avoided entirely:

Opioid Pain Medications — FDA Boxed Warning

This is the most dangerous interaction. Combining Clorazepate with opioids can cause:

• Profound sedation
• Respiratory depression (dangerously slow breathing)
• Coma
• Death

Opioids to watch include:

• Oxycodone (OxyContin, Percocet)
• Hydrocodone (Vicodin, Norco)
• Fentanyl (Duragesic, Subsys)
• Morphine (MS Contin)
• Codeine (Tylenol #3)
• Tramadol (Ultram)

If you must take both a benzodiazepine and an opioid, your doctor should prescribe the lowest effective doses for the shortest possible time and monitor you closely.

Alcohol

Alcohol is a CNS depressant that dramatically amplifies Clorazepate's sedative effects. The combination can cause fatal respiratory depression. There is no safe amount of alcohol to drink while taking Clorazepate.

Other Benzodiazepines

Taking multiple benzodiazepines (for example, Clorazepate plus Alprazolam or Lorazepam) compounds the risks of sedation, respiratory depression, and dependence. This should generally be avoided.

Barbiturates and Sedative-Hypnotics

Medications like Phenobarbital, Secobarbital, and sleep aids like Zolpidem (Ambien) or Eszopiclone (Lunesta) add to CNS depression when combined with Clorazepate.

Antipsychotics

Medications like Chlorpromazine (Thorazine), Quetiapine (Seroquel), and Olanzapine (Zyprexa) can enhance sedation when taken with Clorazepate.

Moderate Drug Interactions

These interactions are less immediately dangerous but can still affect how well Clorazepate works or increase side effects:

Anticonvulsants

• Phenytoin (Dilantin) — Can increase Clorazepate metabolism, potentially reducing its effectiveness
• Phenobarbital — Both a CNS depressant and an enzyme inducer; dual interaction risk
• Carbamazepine (Tegretol) — Increases metabolism of nordiazepam, which may decrease Clorazepate's effects

If you're taking Clorazepate for seizures, your neurologist should be aware of these interactions and may adjust doses accordingly.

Antidepressants

• SSRIs — Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil) — May cause additive sedation
• Tricyclic antidepressants (TCAs) — Amitriptyline (Elavil), Nortriptyline (Pamelor) — Additive drowsiness and sedation

Many people take an antidepressant alongside a benzodiazepine, and this is often manageable with monitoring. Your doctor should know about both medications.

Antihistamines

• Diphenhydramine (Benadryl) — Additive drowsiness. This includes sleep aids that contain diphenhydramine (Tylenol PM, ZzzQuil).
• Hydroxyzine (Vistaril, Atarax) — Also used for anxiety; combining with Clorazepate increases sedation

Muscle Relaxants

Medications like Cyclobenzaprine (Flexeril), Tizanidine (Zanaflex), and Baclofen can cause additive CNS depression with Clorazepate.

CYP Enzyme Inhibitors

These medications can slow down the metabolism of nordiazepam, causing it to build up in your system:

• Cimetidine (Tagamet) — An antacid that inhibits multiple CYP enzymes
• Ketoconazole (Nizoral) — An antifungal that strongly inhibits CYP3A4
• Erythromycin and other macrolide antibiotics

If you start one of these medications while taking Clorazepate, your doctor may need to lower your Clorazepate dose.

Supplements and OTC Medications to Watch

It's easy to overlook over-the-counter products, but several can interact with Clorazepate:

• Melatonin — Additive sedation when combined with benzodiazepines
• Valerian root — Enhances GABA activity and can increase sedation
• Kava — Acts on GABA receptors and can amplify benzodiazepine effects. Cases of liver toxicity have also been reported.
• CBD (cannabidiol) — May increase benzodiazepine levels through CYP enzyme inhibition and add to sedative effects
• St. John's Wort — Can induce CYP enzymes and reduce nordiazepam levels, potentially making Clorazepate less effective
• Diphenhydramine (Benadryl, Tylenol PM, ZzzQuil) — Additive drowsiness, as noted above

Food and Drink Interactions

• Alcohol — Absolutely avoid. Dangerous CNS depression and respiratory depression.
• Grapefruit and grapefruit juice — May increase benzodiazepine levels through CYP3A4 inhibition. While this is more established with some other benzodiazepines, caution is warranted with Clorazepate as well.
• Caffeine — May partially counteract the sedative effects of Clorazepate. This isn't dangerous, but it could reduce the medication's effectiveness for anxiety.

What to Tell Your Doctor

Before starting Clorazepate—or anytime you add a new medication—give your doctor a complete picture:

• All prescription medications you currently take, especially opioids, other benzodiazepines, sleep medications, and antidepressants
• Over-the-counter medications, including antihistamines, sleep aids, and antacids
• Supplements and herbal products, especially melatonin, valerian, kava, CBD, and St. John's Wort
• Alcohol use — Be honest about frequency and amount. Your doctor isn't judging; they need this information to keep you safe
• Recreational drug use — Opioids, cannabis, and other substances can interact dangerously
• Upcoming procedures — If you're having surgery or a dental procedure, tell the anesthesiologist or dentist that you take Clorazepate

Your pharmacist is also an excellent resource. They can run an interaction check every time you fill a new prescription.

Final Thoughts

Clorazepate is an effective medication, but its interaction profile demands respect. The biggest risks come from combining it with opioids, alcohol, or other sedating medications. Being transparent with your healthcare team about everything you take—prescription, OTC, and supplements—is the single most important thing you can do to stay safe.

For more about this medication, explore our guides on Clorazepate side effects and what Clorazepate is and how it's used. And if you need help finding it at a good price, check our savings guide.