Venlafaxine with Phenelzine Interaction Details

Brand Names Associated with Venlafaxine

Brand Names Associated with Phenelzine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 12, 2023

Interaction Effect

CNS toxicity or serotonin syndrome (hypertension, hyperthermia, myoclonus, mental status changes)

Interaction Summary

Serious, sometimes fatal, reactions have been seen with the combination of venlafaxine and monoamine oxidase inhibitors (MAOIs) and concurrent use is contraindicated. Reports of adverse effects have included hyperthermia, rigidity, myoclonus, instability of vital signs, and extreme agitation progressing to delirium and coma. Concurrent use of MAOIs and venlafaxine has also been reported to result in a condition termed serotonin syndrome . Serotonin syndrome is a rare but potentially fatal condition of serotonergic hyperstimulation characterized by changes in mental status, restlessness, myoclonus, hyperreflexia, diaphoresis, shivering, and tremor . In one case serotonin syndrome occurred with initiation of venlafaxine therapy 16 days after discontinuation of phenelzine, suggesting that a longer waiting period may be necessary . In another report, two additional patients were started on venlafaxine at least 14 days after discontinuation of phenelzine and experienced significant serotonin syndrome symptoms .

Severity

Contraindicated

Onset

Rapid

Evidence

Probable

How To Manage Interaction

Concurrent use of venlafaxine and a MAO inhibitor is contraindicated. Wait at least 14 days after discontinuing a MAO inhibitor before initiating therapy with venlafaxine. Wait at least seven days after discontinuing venlafaxine before initiating therapy with a MAO inhibitor. Even if initiating venlafaxine therapy two weeks after discontinuation of phenelzine, monitor patients for development of serotonin syndrome.

Mechanism Of Interaction

Inhibition of serotonin metabolism by monoamine oxidase

Literature Reports

A) Concomitant use of serotonin specific reuptake inhibitors and monoamine oxidase inhibitors can produce a toxic reaction known as serotonin syndrome . Serotonin syndrome is a condition of serotonergic hyperstimulation and manifests as restlessness, myoclonus, changes in mental status, hyperreflexia, diaphoresis, shivering, and tremor. If the syndrome is not recognized and correctly treated, death can result.

B) A 46-year old man with depression was taking a regimen of phenelzine 30 mg three times daily and divalproex 500 mg twice daily. The patient was then told to taper phenelzine before initiating therapy with venlafaxine. The exact tapering regimen was not available. One day after the patient's last dose of phenelzine, the patient took one 37.5 mg tablet of venlafaxine. After 30 to 60 minutes, the patient was confused, twitching, and had a full body tremor. The patient was also having difficulty speaking and was experiencing visual hallucinations. The patient was given propranolol, diphenhydramine, and lorazepam in the emergency room, with subsequent improvement in symptoms. The patient was diagnosed with serotonin syndrome and was transferred to the intensive care unit with resolution of symptoms over the next day without further complications .

C) A 39-year old woman developed symptoms similar to serotonin syndrome due to an interaction between phenelzine and venlafaxine. The patient, who had discontinued a regimen of phenelzine 45 mg daily seven days earlier, took a single 37.5 mg dose of venlafaxine. The patient then experienced diaphoresis, lethargy, lightheadedness, dizziness, agitation, and an elevated creatinine kinase level. After treatment with lorazepam and other supportive therapy, the patient's symptoms resolved. Venlafaxine therapy was successfully initiated a week later at the same dose .

D) A case of serotonin syndrome was reported in a 34-year old man due to an interaction between venlafaxine and phenelzine. The patient had previously been taking phenelzine which was discontinued 16 days before the initiation of therapy with venlafaxine. Shortly after the first venlafaxine dose of 75 mg, the patient experienced symptoms such as agitation, diaphoresis, tachycardia, and muscular rigidity. The patient had a temperature of 98.1 degrees F, a pulse of 115, and a respiratory rate of 16 breaths per minute. After examination revealed hyperreflexia, rigidity, and myoclonus in both feet, the patient was diagnosed with serotonin syndrome. The patient's symptoms resolved over the next 12 hours, and he was prescribed cyproheptadine 8 mg three times daily for two days upon discharge. This case may be of major importance since phenelzine had been discontinued for more than the recommended two weeks before initiation of venlafaxine. A longer washout period may be necessary .

E) A 44-year-old female was stabilized on phenelzine 30 mg twice daily and alprazolam 0.5 mg three times daily when she inadvertently ingested 150 mg of venlafaxine mg along with a dose of phenelzine and alprazolam. Within 45 minutes she began to experience extremity shaking and rapid respirations. On arrival at the hospital, she was agitated, had increased muscle rigidity, increased muscle tone, and diminished verbal responsiveness. Vital signs included blood pressure of 130/58 mm Hg, pulse 148/minute, respirations 24/minute, and a rectal temperature of 38 degrees Celsius. The diagnosis of serotonin syndrome was made. Following intubation and seven days in the intensive care unit, she recovered without any evidence of long-term complications .

F) In a case report on four patients, symptoms of serotonin syndrome were noted, even in two cases where the patients waited 14 days between phenelzine and venlafaxine treatment. The patients ranged in age from 25 to 49 years, and all had been on phenelzine for co-existing migraine and tension-type headaches. The phenelzine was discontinued for various reasons, and three of the four patients had been advised to wait 14 days after stopping phenelzine to start taking venlafaxine. The fourth patient had a hiatus from phenelzine for six days. All the patients experienced symptoms including agitation, shaking, diaphoresis, hyperthermia, slight hypertension, dizziness, weakness, palpitations, and muscle tremors. The onset of the symptoms was within one hour of administration of venlafaxine, and all the patients were returned to baseline within 24 hours of discontinuing the medication .

Venlafaxine Overview

• Venlafaxine is used to treat depression. Venlafaxine extended-release (long-acting) capsules are also used to treat generalized anxiety disorder (GAD; excessive worrying that is difficult to control), social anxiety disorder (extreme fear of interacting with others or performing in front of others that interferes with normal life), and panic disorder (sudden, unexpected attacks of extreme fear and worry about these attacks). Venlafaxine is in a class of medications called selective serotonin and norepinephrine reuptake inhibitors (SNRIs). It works by increasing the amounts of serotonin and norepinephrine, natural substances in the brain that help maintain mental balance.

Phenelzine Overview

• Phenelzine is used to treat depression in people who have not been helped by other medications. Phenelzine is in a class of medications called monoamine oxidase inhibitors (MAOIs). It works by increasing the amounts of certain natural substances that are needed to maintain mental balance.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.