Ondansetron interactions to avoid

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

Ondansetron, known under the brand name Zofran, is a selective 5-HT3 receptor antagonist that functions as an antiemetic to aid in the prevention of nausea and vomiting from chemotherapy or radiation therapy, treatment of severe and acute nausea and vomiting and the prevention and treatment of postoperative nausea and vomiting. Ondansetron is available as an injection, an oral solution, an oral tablet, and an orally-disintegrating tablet. Ondansetron interactions with amiodarone, domperidone, methadone, specific antiarrhythmic and antibiotic medications, and serotonergic agents. Ondansetron can also affect the metabolism of other medicines, exacerbating side effects associated with individual drugs. It’s important to be aware of ondansetron interactions as some of them can cause life-threatening effects after a single dose that warrant immediate medical attention. 

Ondansetron drug interactions

The most serious medications that ondansetron interferes with include certain antiarrhythmics, antibiotics, and serotonergic medications.

Serotonergic Agents

As a selective 5HT3 receptor antagonist, Ondansetron blocks serotonin peripherally and centrally. Therefore, combining with other medications in the 5HT3 receptor antagonist class will increase the potential risk. 

Monoamine oxidase inhibitors, or MAOIs, were the first class of antidepressants developed. These medications work by blocking an enzyme, monoamine oxidase, which removes serotonin from the brain. By inhibiting this enzyme, increased serotonin levels remain available to regulate, allowing feelings of focus, emotional stability, and overall happiness. Some MAOIs have additional indications, like selegiline used as adjunctive therapy for the management of Parkinson’s disease. Other medications inhibit monoamine oxidase as a secondary mechanism to a primary, intended effect. Suppose any medication that inhibits monoamine oxidase is combined with serotonergic drugs like ondansetron. In that case, the serotonergic effect of MAOIs can be enhanced, which could result in a serious medical condition known as serotonin syndrome.

MAOIs include:

• Isocarboxazid (Marplan)
• Phenelzine (Nardil)
• Selegiline (Emsam)
• Tranylcypromine (Parnate)

Additional medications that inhibit monoamine oxidase but are not antidepressants include:

• Methylene blue 
• Linezolid (Zyvox)

Other medications can enhance serotonin in the brain by different mechanisms. MAOIs affect serotonin by slowing its breakdown. They can also impact serotonin by blocking its reabsorption or directly stimulating serotonin receptors, either on purpose or as a secondary effect. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) intentionally raise serotonin levels. It is not advisable to combine medications that increase serotonin simultaneously due to the risk of serotonin syndrome and toxicity. It is important to note that individuals may develop serotonin syndrome and serotonin toxicity on only a single serotonergic agent. Therefore, any onset of symptoms should be managed by immediate communication with a healthcare professional. The prescribing information for ondansetron notes that serotonin syndrome and serotonin toxicity have been reported with the use of 5HT3 antagonists alone or in combination with other serotonergic agents. Therefore, patients combining these prescription drugs should be closely monitored for the emergence of these conditions.

Selective serotonin reuptake inhibitors, in addition to sertraline, include: 

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Paroxetine (Paxil)
• Fluoxetine (Prozac)
• Fluvoxamine
• Vilazodone
• Vortioxetine

Serotonin and norepinephrine reuptake inhibitors (SNRIs) include: 

• Venlafaxine (Effexor)
• Duloxetine (Cymbalta)
• Desvenlafaxine succinate (Pristiq)

Tricyclic antidepressants (TCAs) include:

• Amitriptyline
• Clomipramine
• Desipramine
• Doxepin
• Imipramine
• Lofepramine
• Nortriptyline
• Trimipramine

Other medications with secondary serotonergic effects:

• Lithium
• Fentanyl
• Methadone 
• Tramadol

QT-prolonging Agents

The QT interval is the part of an electrocardiogram (EKG) report that represents the time it takes the heart to contract and recover. Long QT syndromes can be inherited and are the result of an issue with the heart’s electrical conduction such that it takes longer than normal to recharge between heartbeats, which is due to an issue with ion channels and the flow of ions (sodium, calcium, potassium, and chloride) in and out of heart muscle cells to produce electrical activity. Medications can also cause acquired long QT syndrome. When the QT interval is prolonged, the risk for irregular heartbeats like ventricular tachycardias is increased, which can result in cardiac arrest and sudden death due to the heart’s inability to pump blood throughout the body effectively. 

Many medications can independently prolong the QT interval, including: 

Antiarrhythmic medications

• Class IA antiarrhythmics
  • Disopyramide
  • Procainamide
  • Quinidine
• Class III antiarrhythmics
  • Amiodarone
  • Dofetilide
  • Dronedarone
  • Ibutilide
  • Sotalol

Antimicrobials

• Ciprofloxacin
• Levofloxacin
• Ketoconazole
• Fluconazole
• Isavuconazole
• Posaconazole
• Itraconazole
• Voriconazole

Antipsychotics

• Pimozide
• Ziprasidone

Ondansetron demonstrated a mean increase in the QT interval from baseline by 20 milliseconds when given as 4 mg intravenously in the emergency department. Combining the use of other drugs known to prolong the QTc may further increase the risk for serious side effects, with at least one study identifying the use of an additional QT-prolonging drug as the most common risk factor among patients with an identified QT prolongation. Patients prescribed ondansetron, especially those at higher risk for cardiac abnormalities, such as those with heart failure or electrolyte abnormalities (including blood potassium and magnesium levels), should be monitored with an EKG before receiving the first dose. 

Apomorphine

Apomorphine is a dopamine agonist used in the management of Parkinson’s disease, often as adjunctive therapy with other anti-Parkinsonian agents. The combination of ondansetron and other 5HT3 antagonists, including granisetron, dolasetron, and palonosetron, are contraindicated with apomorphine, given the risk of enhanced hypotensive effects. The mechanism of the interaction remains unknown, but apomorphine prescribing information reports cases of profound hypotension and resultant loss of consciousness due to concomitant use of it with ondansetron. 

Tramadol

Tramadol is an opioid analgesic employed in the management of moderate to severe pain. The combination of tramadol and ondansetron may enhance the serotonergic effect of tramadol, increasing the risk of serotonin syndrome or toxicity. In addition to this potential interaction, ondansetron may also decrease the therapeutic effect of tramadol. The presumed mechanism for this decreased analgesic effect between these two medications is thought to involve the antagonism of spinal 5HT3 receptors by ondansetron, which is an effect in opposition to the actions of tramadol, which is suspected to exert some of its pain-relieving effects. 

Metformin

Metformin is a very popular medication prescribed for the management of Type 2 diabetes mellitus. The combination of metformin with ondansetron may increase the blood levels of metformin, such that individuals on concomitant therapy must be monitored for metformin effects or toxicities. A pharmacokinetic study of individuals receiving ondansetron daily demonstrated increased metformin exposure and maximum serum concentrations in 21% of individuals and decreased metformin renal elimination in 36% of participants. This has implications for individuals, including lower blood glucose levels, which can result in serious effects. The mechanism of this interaction is believed to be inhibition of specific transporters in the body by ondansetron, responsible for active renal elimination of metformin.

CYP3A4 inducers

Some ondansetron pharmacologic drug interactions occur due to medications referred to as “CYP3A4 inducers,”-which are medications that increase the activity of a common enzyme (cytochrome P450) involved in the metabolism of many medications, including ondansetron. CYP3A4 inducers are ubiquitous and rev up the enzyme to varying degrees. Strong CYP3A4 inducers include anticonvulsant medications like phenobarbital, phenytoin, and carbamazepine. These medications may decrease the blood levels of ondansetron, but the changes are not considered clinically significant and do not warrant preemptive dose adjustments. 

Other strong CYP3A4 inducers include: 

• Rifampin
• Ketoconazole

Moderate CYP3A4 inducers include:

• Diltiazem
• Erythromycin
• Medications for fungal infections, such as fluconazole, isavuconazole, and posaconazole
• Letermovir
• Verapamil

It’s important to note that these lists are not all-inclusive. Always check with a healthcare professional for any drug-drug interactions. 

Ondansetron food interactions

Ondansetron may be absorbed slightly better when taken with food but can be taken without consideration in meals. Its adverse effects may cause constipation or diarrhea, which, coupled with its indication for nausea and vomiting, may preclude an ability to take with meals. 

Other ondansetron interactions

In addition to prescription drugs, there are also side effects to be aware of with products we may consume without awareness of potential interactions. Knowing how anything you put into your body can interact with another product is important. 

Ondansetron and alcohol 

If you need to take ondansetron, it’s unlikely you’re in the mood to drink alcohol. While there is no immediate interaction, side effects of both may be exacerbated when combined with drowsiness, headache, and agitation. Some dosage forms of ondansetron contain sodium benzoate, a metabolite of benzyl alcohol. Large doses of benzyl alcohol have been associated with potentially fatal toxicity in pediatrics, specifically neonates. Therefore, these formulations of ondansetron should be used with great caution in this population. 

Ondansetron and supplements

Products readily available over the counter may interact with prescription medications like ondansetron. St. John’s wort is a supplement with serotonergic effects that could enhance the ondansetron‘s serotonergic effects. The combination should be taken together with great caution. 

Ondansetron and Phenylketonuria

Phenylketonuria, a medical condition also known as PKU, is an uncommon inherited disorder that results in the accumulation of a specific amino acid called phenylalanine due to a change in the gene that creates the enzyme needed to break down phenylalanine. The buildup of this amino acid can result in long-term intellectual disabilities, so afflicted individuals must follow a diet that limits phenylalanine. Ondansetron orally disintegrating (Zofran ODT) tablets contain phenylalanine, so its use must be avoided in those affected individuals living with phenylketonuria. 

How to minimize ondansetron interactions

Always carry a complete list of medications, including those that are non-prescription. Any time you’re receiving medical advice with new therapy recommendations, provide this list to help minimize the risk of drug interactions. When starting a new medication, reading the included drug information and discussing any new signs or symptoms with your healthcare professional is advisable, no matter how mild. 

When to talk to a healthcare provider about ondansetron interactions

This article is only a partial list of ondansetron interactions. Be mindful of the risk of additive side effects and direct drug interactions, which may occur when ondansetron is used in combination with prescription and over-the-counter medications or supplements. Communicate directly with a healthcare professional anytime you require ondansetron 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.