Alprazolam interactions to avoid

Drug interactions | Food interactions | Other interactions | Avoiding interactions | When to see a doctor

Alprazolam is a benzodiazepine that is approved by the U.S. Food and Drug Administration (FDA) to manage generalized anxiety disorder. It is also used off-label for other forms of anxiety, like agoraphobia, panic disorders, and acute vertigo episodes. Other benzodiazepines include clonazepam, diazepam, and lorazepam. Xanax is the brand name of the medication, but it is readily available as a generic formulation in an oral concentrate solution, tablets, orally disintegrating tablets, and extended-release tablets. Alprazolam is an important member of the armamentarium of medications for mental health disorders. Still, it is a controlled substance and comes with the risk of drug abuse and physical dependence. Abruptly stopping alprazolam in those with physical dependence can result in withdrawal symptoms, like restlessness, insomnia and other sleep disturbances, irritability, and poor concentration. Alprazolam also causes central nervous system (CNS) adverse effects like sedation, drowsiness, fatigue, and confusion, so many drug interactions will arise when used with other medications with similar effects, including opioids. In addition to CNS depressants, other medications that interact with alprazolam include CYP3A4 inhibitors and inducers and Selective Serotonin Reuptake Inhibitors (SSRIs). 

RELATED: Xanax side effects and how to avoid them

Alprazolam drug interactions

Alprazolam’s most serious drug interactions arise with opioids, certain antidepressants, muscle relaxants, and other CNS depressants due to the additive risk of side effects like slowed breathing. Other medications interact with alprazolam metabolism, such as azole antifungals, macrolide antibiotics, anticonvulsants, and miscellaneous medications from various drug classes.

Opioids

Opioids are prescribed for persistent chronic pain and are usually not as first-line therapy. They are CNS depressants and alone may result in serious side effects, including respiratory depression (slowed breathing) and death. An FDA drug safety communication described that combining opioids with benzodiazepines like alprazolam has resulted in serious adverse events related to the additive CNS depression contributed by both types of medication. This warning came from studies like those that demonstrated a 10-fold higher risk of opioid-related death in individuals who also received benzodiazepines. Combinations of opioids with benzodiazepines should be done judiciously and potentially only under conditions with close monitoring of the individual by a medical professional, given the life-threatening implications. 

Selective Serotonin Reuptake Inhibitors (SSRIs)

CNS depressants like alprazolam may enhance the adverse and sometimes toxic effects of SSRIs. The combination is not an absolute contraindication and generally only requires increased monitoring and cognizance of specifically enhanced psychomotor impairment. Individuals receiving alprazolam with an SSRI require thorough education from a healthcare provider to exercise caution when operating automobiles and other hazardous machinery until it is known how the combination affects them. This warning will be included in the prescribing information of these SSRIs. 

SSRIs that may interact with alprazolam in this way include:

• Citalopram
• Fluoxetine
• Escitalopram
• Fluoxetine
• Paroxetine
• Sertraline

Anticonvulsants 

Some anticonvulsants may interact with alprazolam. While alprazolam is a substrate of CYP3A4, it is also a weak inhibitor. Anticonvulsants metabolized by CYP3A4, like carbamazepine, may increase the anticonvulsant levels when combined with alprazolam. Prescribing information of carbamazepine recommends against coadministration of CYP3A4 inhibitors. If taken together, individuals should be monitored for increased risk of carbamazepine toxicity, which includes ataxia, drowsiness, vertigo, and diplopia. Doses of carbamazepine may need to be decreased.

Individuals receiving CYP3A4 enzyme-inducing anticonvulsants with alprazolam, like phenytoin and phenobarbital, may result in decreased blood levels of alprazolam. If the combination cannot be avoided, individuals and their caregivers should be educated on the risk of increased symptoms of anxiety disease while receiving the combination. 

Miscellaneous CNS depressants

Other CNS depressants, like skeletal muscle relaxants and sleep aids like zolpidem, can also increase the risk of injuries due to falls and hospitalization among older adults, especially when taken in combination with benzodiazepines. 

Azole Antifungals

Azole antifungals are considered moderate to strong inhibitors of CYP3A4, a hepatic enzyme responsible for alprazolam’s metabolism from its pharmacologically active state to therapeutically inactive metabolites that are then eliminated from the body. This combination can, therefore, increase the blood levels of alprazolam, increasing the risk of the intensity and duration of serious side effects associated with its use. Ketoconazole, a potent CYP3A4 inhibitor, has been shown to increase alprazolam exposure by 2 to 4 times when administered together. Alprazolam prescribing information states that coadministration with strong CYP3A4 inhibitors is a contraindication. 

Azole antifungals that may interact with alprazolam include:

• Ketoconazole
• Isavuconazole
• Posaconazole
• Itraconazole
• Voriconazole

Macrolide Antibiotics

Macrolide antibiotics are considered strong inhibitors of the hepatic enzyme CYP3A4, which alprazolam depends upon for its metabolism to an inactive metabolite. The combination of alprazolam and strong CYP3A4 inhibitors is listed as a contraindication due to the risk of increased serious side effects of alprazolam, including significantly depressed respiratory and psychomotor function. These effects have been demonstrated to last for days after initiation of clarithromycin. Benzodiazepines that do not rely on cytochrome metabolic pathways may be considered alternatives to alprazolam, such as lorazepam and oxazepam. 

Macrolide antibiotics that may interact with alprazolam include:

• Azithromycin
• Clarithromycin
• Erythromycin

Miscellaneous CYP3A4 inhibitors

Other CYP3A4 inhibitors that should be avoided while taking alprazolam include fluvoxamine, cimetidine, ritonavir, and nefazodone. Considerations of alternate agents should be pursued, and if no alternatives are available, then individuals should be counseled on the interaction and its implication on increased side effects related to the benzodiazepine. 

Alprazolam food interactions

Alprazolam and grapefruit

Grapefruit and its juice interact with many prescription drugs. It is known through scientific studies to inhibit the enzyme CYP3A4 in the metabolism of many medications. CYP3A4 plays a role in metabolizing more than 65% of all drugs. When grapefruit juice inhibits the action of the enzyme, more of the drug is available to remain in the blood and throughout the body. 

Alprazolam is dependent on this enzyme for its metabolism. Therefore, acute increases in the consumption of grapefruit juice may increase the blood concentrations of alprazolam. It is best to consume the same moderate amount of grapefruit juice consistently when on alprazolam or avoid grapefruit juice entirely. 

Other alprazolam interactions

Alprazolam may interact with alcohol and certain supplements and carry some additional risk of side effects in individuals with certain medical conditions. 

Alprazolam and alcohol 

Alcohol interacts with many prescription drugs, and alprazolam is one of them. Some of the common side effects of alprazolam include impairment of cognitive or motor performance, so there is great concern that combining this medication with alcohol may cause further enhancement of these potential side effects. In addition, alcohol can make the mental condition being managed with alprazolam worse, such as anxiety, fatigue, and irritability.

Alprazolam and caffeine

While there is no direct interaction between alprazolam and caffeine, caffeine consumption can worsen the symptoms of anxiety, and excess intake of caffeine may be beneficial in controlling symptoms.

Alprazolam and St. John’s wort

St. John’s wort is a supplement used for effects on depression but can cause interactions with many medications. St. John’s wort does interact with alprazolam, resulting in decreased levels of alprazolam. This could affect the symptoms for which alprazolam is consumed, and concomitant use should be avoided. 

Alprazolam and Kava Kava

Kava kava has been used in the Pacific Islands for its depressant effects. Its effects specifically are described as similar to alcohol, resulting in a state of relaxation. Kava is a tall shrub, and the root of this plant is used medicinally to treat anxiety and insomnia, among other mental health conditions. Kava kava may enhance the CNS depressant effect of alprazolam, and combining multiple agents with the same effects should be approached cautiously. 

Alprazolam and glaucoma

Benzodiazepines like alprazolam can result in dilation of the pupil in the eye, so it may cause problems in individuals with the medical condition narrow-angle glaucoma. The same concern is absent for those with open-angle glaucoma. Those unsure of which form of glaucoma they have should check with their ophthalmologist before beginning alprazolam. 

Alprazolam and obesity

In obese patients, the half-life of alprazolam may be prolonged, given the increased distribution into fat. Alprazolam should be dosed judiciously in these individuals, with caution taken and increased monitoring of side effects. The frequency of redosing may need to be reduced in obese patients. 

How to minimize alprazolam interactions

Always carry a complete list of medications, including supplements, on your person. Any time you’re inquiring about medical advice, provide this list so that a thorough review and drug information assessment can be performed to minimize the risk of drug interactions. Whenever you begin a new medication, even if symptoms are mild, you should discuss them with your healthcare professional. 

When to talk to a healthcare provider about alprazolam interactions

This article is not a complete list of alprazolam interactions. Be mindful of the risk of additive side effects and direct drug interactions, which may occur when benzodiazepines are used in combination with prescription and over-the-counter medications. Communicate directly with a healthcare professional anytime you begin taking alprazolam so that a comprehensive review of interactions of both medications, diet, and conditions can occur to ensure a proper monitoring plan is put in place.