Benadryl, St. John’s Wort, and More: 8 Guanfacine Interactions to Watch Out For

Guanfacine is an oral medication that comes in two different forms: an immediate-release (IR) tablet to treat hypertension (high blood pressure) and an extended-release (ER) tablet to treat attention-deficit hyperactivity disorder (ADHD). Both forms are available as generic medications, but guanfacine ER also comes as the brand-name medication Intuniv. 

Before starting treatment with guanfacine, ask your prescriber and pharmacist about potential drug interactions. Giving them a list of your current medications will allow them to assess your individual risk.

Guanfacine interactions summary

The following medications and substances can interact with guanfacine:

• Sleep medications, such as zolpidem (Ambien) 

• Antihistamines, such as diphenhydramine (Benadryl, ZzzQuil)

• Benzodiazepines, such as alprazolam (Xanax)

• Opioids, such as oxycodone (Roxicodone, OxyContin)

• Muscle relaxers, such as carisoprodol (Soma)

• Antipsychotics, such as olanzapine (Zyprexa)

• Some anti-seizure medications, including carbamazepine (Tegretol, Equetro) and phenytoin (Dilantin, Phenytek)

• Some antibiotics, including ciprofloxacin (Cipro) and rifampin (Rifadin)

• Some antiretrovirals, including those containing ritonavir (Norvir) or cobicistat (Tybost)

• Some antifungals, including fluconazole (Diflucan)

• Calcium channel blockers, such as verapamil

• Alcohol

• St. John’s wort

• Grapefruit juice

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Keep in mind that this is not a comprehensive list of potential interactions. So make sure to talk with your prescriber anytime you start or stop a new medication while taking guanfacine.

And keep reading to learn more about eight notable guanfacine interactions, which we discuss in detail below.

1. Medications that cause drowsiness, such as Benadryl

One of the most common guanfacine side effects is drowsiness. You may be able to manage drowsiness from the medication by taking your doses at night. But if you take guanfacine with other medications that can make you sleepy, this side effect can be more intense. 

Examples of medications that cause drowsiness include:

• Sleep medications, such as zolpidem

• Antihistamines, such as diphenhydramine, doxylamine (Unisom Sleep Tabs), and hydroxyzine (Vistaril)

• Benzodiazepines, such as alprazolam

• Opioids, such as oxycodone

• Muscle relaxers, such as carisoprodol

• Antipsychotics, such as olanzapine

Talk with your prescriber and pharmacist about whether you take any medications that can cause drowsiness and could interact with guanfacine. 

EXPERT PICKS: WHAT TO READ NEXT

• Guanfacine side effects: Learn about common and rare side effects to watch out for while taking guanfacine.

• Tips for taking guanfacine: Taking guanfacine correctly, which includes avoiding high fat meals with extended-release doses, is important to getting the most out of the medication.

• Strattera vs. Intuniv: Learn about these two nonstimulant ADHD medications and how they compare.

When you first start treatment, it’s a good idea to avoid driving and other activities that require alertness until you see how guanfacine affects you — especially if you take other medications that cause drowsiness. If you experience intense drowsiness, your prescriber may adjust your medication regimen.

2. Alcohol

Alcohol can have many different effects on the body, including drowsiness. Combining alcohol with guanfacine can make you feel more sleepy. This is especially dangerous if you’re doing activities you need to be alert for.

Many experts believe that, in general, there’s no safe amount of alcohol to drink. And it’s typically recommended to avoid alcohol while taking guanfacine. So if you drink alcohol, talk to your prescriber about whether guanfacine is safe to take. They can help you understand your individual risks.

3. Certain anti-seizure medications, such as carbamazepine

Anti-seizure medications treat seizure disorders (epilepsy). Many of these medications have several potential drug interactions. This is because they affect liver proteins (enzymes) that metabolize (break down) other medications.

Some anti-seizure medications, including carbamazepine and phenytoin, can lower levels of guanfacine in the body. They do this by speeding up how quickly guanfacine is metabolized. This can make guanfacine less effective at treating hypertension and ADHD.

If you take an anti-seizure medication like carbamazepine or phenytoin, your prescriber may adjust your guanfacine dosage. Whether you started taking guanfacine before or after one of these medications will determine how they adjust your dosage.

4. St. John’s wort

St. John’s wort is an herbal supplement that some people use to help with depression and other health conditions. However, it’s well known for its potential to interact with medications. This is because it enhances liver enzymes, speeding up the metabolism of certain medications, including guanfacine.

If you take St. John’s wort, talk to your prescriber before starting treatment with guanfacine. They may recommend avoiding the combination if possible. Or they may adjust your guanfacine dosage. 

Additionally, if you wish to start or stop taking St. John’s wort while taking guanfacine, don’t do so before talking to a healthcare professional.

5. Some antibiotics, such as ciprofloxacin

Some antibiotics can interact with guanfacine. This can happen in two ways:

1. Antibiotics like rifampin enhance enzymes that metabolize guanfacine. This may lead to decreased levels of guanfacine and possibly decreased effectiveness. If you need to take rifampin while taking guanfacine, you may need a higher guanfacine dosage.

2. Antibiotics like clarithromycin (Biaxin XL), erythromycin, and ciprofloxacin can slow down guanfacine metabolism. This can lead to increased blood levels of guanfacine and increased side effects. If you need to take one of these antibiotics with guanfacine, you may need a lower guanfacine dosage.

Let your prescriber know if you’re taking an antibiotic before you start treatment with guanfacine. And let them know if you plan to start or stop taking an antibiotic anytime during treatment.

6. Some antivirals, such as ritonavir

Antiviral medications that treat conditions like HIV and COVID-19 can interact with guanfacine. Specifically, medications that contain ritonavir or cobicistat can block liver enzymes that metabolize guanfacine. This can increase guanfacine blood levels, raising your risk of side effects. 

Examples of combination medications that include ritonavir or cobicistat include:

• Nirmatrelvir / ritonavir (Paxlovid)

• Lopinavir / ritonavir (Kaletra)

• Elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide (Genvoya)

• Darunavir / cobicistat (Prezcobix)

On the other hand, some antivirals can decrease guanfacine levels in the body, making the medication less effective. This includes etravirine (Intelence) and medications containing efavirenz, such as Atripla (efavirenz / emtricitabine / tenofovir) and Symfi (efavirenz / lamivudine / tenofovir).

If you need antiviral treatment for HIV or COVID, check with your prescriber. They may suggest adjusting your guanfacine dosage or monitoring for new or worsening side effects. Or they may suggest an alternative to guanfacine.

7. Some antifungals, such as fluconazole

Azole antifungals treat several types of fungal infections. But a few of these antifungals can interact with guanfacine by blocking enzymes that metabolize the medication. This can increase levels of guanfacine in the body and raise the risk of side effects. 

Examples of antifungals that can interact with guanfacine include:

• Ketoconazole oral tablets

• Fluconazole

• Itraconazole (Sporanox)

You may need to take a lower dosage of guanfacine if you’re being treated with one of these medications. Your prescriber can help determine the best course of action for your situation.

8. Some calcium channel blockers, including diltiazem and verapamil

Calcium channel blockers treat hypertension and other heart conditions. These medications lower blood pressure, and some, like diltiazem (Cardizem) and verapamil, can also decrease heart rate. As a result, they can cause blood pressure and dizziness, which are also possible side effects of guanfacine. So combining guanfacine with calcium channel blockers could make these side effects more likely.

What’s more, diltiazem and verapamil also block liver enzymes that metabolize guanfacine. This can lead to higher guanfacine levels in the body and further increase the risk of side effects.

Your prescriber may suggest avoiding diltiazem and verapamil while taking guanfacine. Or they may ask you to watch for increased side effects. You may also be asked to check your blood pressure and heart rate at home more often.

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Written by:

Austin Ulrich, PharmD, BCACP

Austin Ulrich, PharmD, BCACP, is a board-certified ambulatory care clinical pharmacist. In his early career, he provided direct patient care in a variety of settings, including hospital and community pharmacies, and in a primary care clinic as a clinical pharmacist.

Edited by:

Amy B. Gragnolati, PharmD, BCPS

Amy Gragnolati, PharmD, BCPS, is a pharmacy editor for GoodRx. Amy currently holds her pharmacist license in Georgia and California.

Reviewed by:

Soojin Jun, PharmD

Soojin has 10 years of experience in various pharmacy settings, from inpatient to outpatient settings, and population health in value-based healthcare models. She completed training in various areas of healthcare to ensure patient safety, from activism, geriatric pharmacy, medication safety, healthcare quality, patient safety, death and dying, and trauma-informed care.

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