Xanomeline, an investigational drug that acts on muscarinic receptors, is not available on its own due to significant peripheral side effects. Instead, it is approved for use in the combination therapy Cobenfy (also known as KarXT), where xanomeline is paired with trospium, a muscarinic antagonist that works to counteract the peripheral effects. Most of the side effects associated with xanomeline are therefore linked to this combination therapy and are primarily gastrointestinal in nature. While these are often mild and temporary, it is important for patients and healthcare providers to be aware of the full range of potential adverse events.
Common Gastrointestinal Side Effects
Clinical trial data from the EMERGENT program have identified a number of common, mostly mild-to-moderate gastrointestinal (GI) side effects associated with xanomeline/trospium. For many patients, these symptoms are most pronounced during the first couple of weeks of treatment and tend to subside over time.
- Nausea: Reported by up to 19% of patients in clinical trials, this is one of the most frequent side effects.
- Indigestion (Dyspepsia) and Heartburn (GERD): Also very common, affecting a notable portion of users.
- Constipation: Occurs in a significant number of patients, and unlike some other GI issues, can sometimes persist throughout treatment.
- Vomiting: Experienced by many patients, particularly during the initial phase of treatment.
- Diarrhea and Abdominal Pain: Less common than nausea but still reported frequently in trials.
- Dry Mouth and Excessive Salivation: While trospium helps mitigate the excessive salivation caused by xanomeline, some patients may still experience either dry mouth or, less commonly, increased salivation.
Cardiovascular and Nervous System Side Effects
Beyond GI discomfort, xanomeline/trospium can also affect the cardiovascular and nervous systems. These effects are also generally mild but warrant attention.
Cardiovascular Adverse Reactions
- Hypertension (High Blood Pressure): An increase in blood pressure has been observed in some patients.
- Tachycardia (Increased Heart Rate): Fast or irregular heart rate is another potential side effect that should be monitored, particularly at baseline and during dose changes.
- Dizziness and Postural Hypotension: Some individuals may experience dizziness or lightheadedness, particularly when rising suddenly.
Central Nervous System (CNS) Effects
- Dizziness and Somnolence (Sleepiness): Dizziness and sleepiness are common, especially when first starting the medication. Patients are advised to use caution when driving or operating machinery until they understand how the drug affects them.
- Confusion and Hallucinations: In some cases, CNS anticholinergic effects can lead to confusion or hallucinations. These may require dose reduction or discontinuation.
- Blurred Vision: Ocular side effects, including blurred vision, have been reported.
Serious and Less Common Adverse Effects
While infrequent, some side effects require immediate medical attention.
- Angioedema: A rare but potentially life-threatening allergic reaction involving swelling of the face, lips, tongue, or throat, which can cause breathing difficulties.
- Urinary Retention: Trospium can cause difficulty in completely emptying the bladder. This is a particular concern for older adults or those with pre-existing conditions like an enlarged prostate and can increase the risk of urinary tract infections.
- Narrow-Angle Glaucoma: The medication can cause pupillary dilation, which may trigger an acute angle-closure attack in individuals with untreated narrow-angle glaucoma. Symptoms include eye pain, blurred vision, and seeing halos around lights.
- Hepatobiliary Problems: Liver injury, indicated by signs like jaundice (yellowing of the skin or eyes), dark urine, and upper abdominal pain, has been reported. Not recommended for patients with moderate to severe liver impairment.
Comparing Xanomeline's Side Effect Profile to Traditional Antipsychotics
Xanomeline's mechanism of action, targeting muscarinic receptors rather than dopamine receptors, gives it a distinct side effect profile compared to typical antipsychotic drugs.
| Side Effect Category | Xanomeline/Trospium (Cobenfy) | Traditional Antipsychotics (e.g., Risperidone, Olanzapine) |
|---|---|---|
| Weight Gain | Minimal; trials show average weight loss. | Commonly associated with significant weight gain. |
| Metabolic Issues | Minimal metabolic dysfunction (e.g., changes in cholesterol, A1C). | High risk of metabolic syndrome, including elevated blood sugar and lipids. |
| Extrapyramidal Symptoms (EPS) | Low incidence of movement disorders like muscle stiffness, restlessness, and tremors. | Higher risk, especially with first-generation antipsychotics. |
| Gastrointestinal Effects | High incidence of nausea, constipation, dyspepsia, especially early in treatment. | Vary depending on the medication; some can cause constipation or GI upset. |
| CNS Effects | Dizziness, sleepiness, potential for confusion, hallucinations. | Drowsiness is common; other CNS effects can occur. |
Managing Xanomeline Side Effects
Managing the side effects of xanomeline/trospium often involves adjusting the dose or timing of the medication. Healthcare providers typically start patients on a lower dose and gradually increase it, which can help minimize initial GI symptoms.
- For gastrointestinal upset, timing the medication correctly can be effective. It is recommended to take it on an empty stomach, at least one hour before or two hours after a meal.
- For persistent constipation, managing it with other medications or dietary changes may be necessary.
- If cardiovascular or more severe CNS symptoms arise, the dose may need to be adjusted or the medication discontinued under medical supervision.
Conclusion
Xanomeline, available as part of the combination therapy Cobenfy (xanomeline/trospium), offers a new approach to treating schizophrenia with a different side effect profile than traditional antipsychotics. While common side effects like nausea, constipation, and dizziness are frequent, they are often mild, transient, and more manageable than the significant weight gain and metabolic issues associated with older medications. Crucial awareness of serious but less common adverse effects, including angioedema, urinary retention, and potential for narrow-angle glaucoma, is essential for patient safety. Ultimately, close collaboration with a healthcare provider is vital to manage side effects and optimize treatment outcomes for each individual.
Visit Cobenfy's official website for more information on the medication.
