8 Clozapine Interactions to Consider (Plus Other Medications to Avoid)

Clozapine (Clozaril) is an atypical antipsychotic medication. It’s FDA approved for adults who have schizophrenia. It’s prescribed when other antipsychotics haven’t worked well enough. Clozapine can also help reduce suicidal thoughts in people with schizophrenia or schizoaffective disorder.

Clozapine can be an effective treatment. But it also comes with many risks. Drug interactions are one thing to keep in mind if you or a loved one is taking this medication. Clozapine interacts with many medications, dietary supplements, and substances. Some interactions can worsen side effects. Others can make clozapine less effective.

Here, we’ll review eight notable clozapine interactions in more detail.

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1. Certain antidepressants

Antidepressants are sometimes prescribed along with antipsychotics to help treat depressive symptoms. But certain antidepressants may raise clozapine levels in the body. This can increase the risk of clozapine side effects.

Antidepressants that interact with clozapine in this way include:

• Selective serotonin reuptake inhibitors (SSRIs), such as fluvoxamine (Luvox), paroxetine (Paxil), and fluoxetine (Prozac)

• Serotonin and norepinephrine reuptake inhibitors, such as duloxetine (Cymbalta)

• Bupropion (Wellbutrin XL)

Some small studies suggest citalopram (Celexa) may be the SSRI that’s least likely to affect clozapine levels. But it causes some of the same side effects as clozapine, such as nausea and increased sweating. These side effects may be worse if you’re taking both.

At times, the benefits of combining clozapine with antidepressants outweigh the risks. So even though they do interact, your prescriber may still recommend you take both. They will likely watch for clozapine side effects, especially when you start the combination.

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2. Erythromycin

Erythromycin (Ery-Tab) is an antibiotic that can treat a variety of infections. It can increase clozapine levels in the body, which could raise your risk of side effects. In some studies, people taking erythromycin and clozapine experienced sleepiness, disorientation, and seizures.

Your prescriber will likely recommend a different antibiotic if that’s an option.

3. Ciprofloxacin

Ciprofloxacin (Cipro) is another antibiotic. It can also increase clozapine levels and make side effects more likely. But unlike erythromycin, ciprofloxacin may raise clozapine blood levels to toxic levels. Your prescriber will likely avoid this combination if at all possible.

If you need to take ciprofloxacin, a lower clozapine dosage is recommended while taking the antibiotic. Your prescriber might also check your clozapine blood levels during this time. But you should not change your clozapine dosage on your own. Your prescriber will help you determine if you should make a change.

4. Many hormonal birth controls

Many forms of hormonal birth control also interact with clozapine. This includes birth control pills, patches, and rings. The hormones in these birth controls can increase clozapine levels. This can lead to more side effects. In some studies, taking clozapine with these birth control methods led to low blood pressure, tremors, and drowsiness.

But not all birth control interacts with clozapine. The following aren’t known to have this effect:

• Hormonal intrauterine devices (IUDs), such as Mirena (levonorgestrel)

• Paragard (the copper IUD)

• Nexplanon (etonogestrel), the birth control arm implant

• Medroxyprogesterone (“the Depo shot”)

You may want to consider discussing these birth control methods with your prescriber. Even if they’re not an option for you, you may be able to take other forms of hormonal birth control. In this case, your prescriber may adjust your clozapine dose or keep an eye on your clozapine levels.

5. Medications that contain ritonavir, such as Paxlovid

Ritonavir (Norvir) is an antiviral that’s in some HIV medications and the COVID-19 treatment Paxlovid (nirmatrelvir / ritonavir). Ritonavir can raise clozapine levels in the body. In some  reports, people experienced very low white blood cell counts (agranulocytosis) with this combination.

Agranulocytosis is a serious side effect of clozapine. It can raise your risk of developing severe or life-threatening infections. Because of this, regular absolute neutrophil count (ANC) tests are required while taking clozapine. If your ANC drops too low, you may need to stop the medication until your levels return to a safe range.

If you’re taking ritonavir as part of HIV treatment, you may be prescribed both medications. In this case, your prescriber will likely keep a close eye on your ANC. But it’s not recommended to take Paxlovid if you take clozapine. There are other COVID treatments available that don’t have this interaction.

6. Carbamazepine

Carbamazepine (Tegretol, Equetro) is a seizure medication that’s also approved for bipolar 1 disorder and certain types of nerve pain. It’s not recommended to take both carbamazepine and clozapine.

Both carbamazepine and clozapine have a risk of lowering white blood cell counts. When combined, your risk of agranulocytosis goes up. What’s more, carbamazepine can lower levels of clozapine in the body. So clozapine may be less effective.

It’s unlikely that a healthcare professional would prescribe both clozapine and carbamazepine. Other treatments for seizures, bipolar 1 disorder, and nerve pain are safer to take with clozapine.

7. St. John’s wort

St. John’s wort is an over-the-counter (OTC) supplement that people sometimes take to relieve symptoms of depression. But this supplement has several drug interactions. St. John’s wort can lower clozapine levels and make it less effective. In some reports, people taking clozapine experienced worsening mental health symptoms after starting St. John’s wort.

Since St. John’s wort is available without a prescription, your healthcare team may not know you’re taking it. Be sure to include OTC medications, vitamins, and supplements on your medication list. Always ask your prescriber and pharmacist about interactions before starting new OTC products.

8. Smoking

Smoking is one clozapine interaction that’s often overlooked. This interaction isn’t caused by the substance you’re smoking, such as nicotine or tobacco. Instead, it’s caused by chemicals in the cigarette, vape, or other item you’re smoking. This clozapine interaction becomes a problem when someone changes their smoking habits.

It’s recommended for everyone to quit smoking. But if you take clozapine, develop a plan for stopping with your prescriber. Quitting smoking can cause your clozapine levels to rise and may cause side effects. Your prescriber can provide you with dosage changes and help you stop smoking safely.

If you start or increase your amount of smoking, be honest about it with your prescriber. Clozapine levels decrease when your smoking increases. This can make the medication less effective. You may need your clozapine dosage raised in this case.

Other clozapine interactions to be aware of

We highlighted only some of the most notable clozapine interactions above. But there are other interactions. Keep in mind that these may raise the risk of clozapine side effects or make it less effective.

Other clozapine interactions include:

• Alcohol

• Amiodarone (Pacerone)

• Benztropine

• Caffeine (in large amounts)

• Cimetidine (Tagamet)

• Cyclobenzaprine

• Diphenhydramine (Benadryl)

• Other antipsychotics, such as quetiapine (Seroquel)

• Phenytoin (Dilantin, Phenytek)

• Rifampin (Rifadin)

• Terbinafine

This isn’t a complete list of all the possible clozapine interactions. Share an updated medication list with your prescriber and pharmacist. That can help them pinpoint and manage interactions.

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Written by:

Victoria Dadebo, PharmD, BCPS

Victoria Dadebo is a freelance pharmacy writer who began contributing to GoodRx in 2022. She has experience in both community and hospital settings, and she is furthering her pharmacy training to specialize in mental health.

Edited by:

Christina Aungst, PharmD

Christina Aungst, PharmD, is a pharmacy editor for GoodRx. She began writing for GoodRx Health in 2019, transitioning from freelance writer to editor in 2021.

Reviewed by:

Tegan Smedley, PharmD, APh

Tegan Smedley, PharmD, APh, has 10 years of experience as a pharmacist. She has worked in a variety of settings, including retail, hospital, and ambulatory care.

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