Xanomeline

BRAND NAMES

COBENFY –xanomeline and trospium chloride.

KarXT – Former development name of the xanomeline–trospium combination.

MECHANISM OF ACTION

Xanomeline acts as a muscarinic acetylcholine receptor agonist, mainly stimulating M1 and M4 receptors in the central nervous system. It activates these receptors in the brain and helps regulate neurotransmitter activity, particularly dopamine and glutamate pathways. This improves neuronal communication and helps reduce symptoms of schizophrenia. Unlike traditional antipsychotic drugs, xanomeline does not directly block dopamine D2 receptors. It is combined with trospium chloride, which blocks peripheral muscarinic receptors to reduce unwanted cholinergic side effects.

PHARMACOKINETICS

Absorption

Xanomeline is administered orally in combination with trospium chloride and is absorbed through the gastrointestinal tract into the bloodstream. Following oral administration, it reaches its maximum plasma concentration (Tmax) in approximately 2 hours. Food has a minimal effect on the absorption of xanomeline, although a high-fat meal may increase its overall exposure (AUC) by approximately 30%. The drug shows dose-dependent increases in plasma concentration and reaches steady-state levels within approximately 3–5 days of regular administration. It is recommended to take the combination medicine on an empty stomach as prescribed.

Distribution

Xanomeline is widely distributed throughout the body after absorption into the bloodstream. It has a large apparent volume of distribution of approximately 10,800 litres, indicating extensive distribution into body tissues. It shows high plasma protein binding of approximately 95%. The drug is distributed into various tissues, including the central nervous system, where it acts on muscarinic M1 and M4 receptors in the brain. This distribution helps xanomeline produce its therapeutic effects in patients with schizophrenia.

Metabolism

Xanomeline is extensively metabolized in the liver after oral administration. Its metabolism occurs mainly through the cytochrome P450 (CYP450) enzyme system, particularly CYP2D6, CYP2B6, CYP1A2, CYP2C9 and CYP2C19. It is also metabolized by flavin-containing monooxygenase enzymes, mainly FMO1 and FMO3. These metabolic processes convert xanomeline into different metabolites before elimination from the body. Liver function plays an important role in its metabolism, and patients with hepatic impairment may experience increased drug exposure. Therefore, liver function should be assessed before and during treatment when clinically indicated.

Elimination

Xanomeline is eliminated from the body mainly through urine and feces after undergoing extensive metabolism in the liver. Approximately 78% of the administered dose is excreted through urine, mainly in the form of metabolites, while about 12% is eliminated through feces. Less than 0.01% of the drug is excreted unchanged in urine. Xanomeline has an elimination half-life of approximately 5 hours and an apparent clearance of about 1950 L/hour. The drug is removed from the body through metabolic processes followed by renal and fecal excretion.

PHARMACODYNAMICS

Xanomeline is a muscarinic acetylcholine receptor agonist that acts mainly on M1 and M4 receptors in the central nervous system. It stimulates these receptors in the brain and helps regulate neurotransmitter activity, including dopamine and glutamate signalling. Activation of M1 receptors supports cognitive functions such as memory, attention and learning, while activation of M4 receptors helps regulate dopamine activity and reduce psychotic symptoms. Unlike conventional antipsychotic drugs, xanomeline does not directly block dopamine D2 receptors. It helps improve positive and negative symptoms of schizophrenia through the cholinergic pathway. Xanomeline is combined with trospium chloride, which blocks peripheral muscarinic receptors and reduces unwanted cholinergic side effects such as nausea, vomiting, sweating and increased salivation.

ADMINISTRATION

Xanomeline is administered orally in combination with trospium chloride as a capsule formulation under the brand name COBENFY. It is usually taken twice daily, once in the morning and once in the evening, on an empty stomach with water. The medication should be taken at least one hour before meals or at least two hours after meals. The capsule should be swallowed whole without crushing, chewing or opening. The dosage is gradually increased according to the patient's response and tolerance under medical supervision.

DOSAGE AND STRENGTH

Xanomeline is available in combination with trospium chloride under the brand name COBENFY as oral capsules. The available strengths are 50 mg/20 mg, 100 mg/20 mg and 125 mg/30 mg (xanomeline/trospium chloride). The recommended starting dose is 50 mg/20 mg twice daily for at least 2 days, followed by 100 mg/20 mg twice daily for at least 5 days. Depending on the patient's response and tolerability, the dosage may be increased to 125 mg/30 mg twice daily. The maximum recommended adult dose is 125 mg/30 mg twice daily. In elderly patients, slower dose titration may be required, with a maximum dose of 100 mg/20 mg twice daily.

DRUG INTERACTIONS

Xanomeline, when combined with trospium chloride, may interact with several medications and affect their therapeutic activity. Strong CYP2D6 inhibitors may increase xanomeline levels in the blood and increase the risk of adverse effects. Concurrent use with other antimuscarinic drugs may increase anticholinergic side effects such as dry mouth, constipation, blurred vision and urinary retention. Drugs eliminated through renal tubular secretion may increase the concentration of trospium chloride in the body. Xanomeline may also increase the blood levels of certain medicines that are substrates of CYP3A4 and P-glycoprotein, potentially increasing their adverse effects.

FOOD INTERACTIONS

Xanomeline is administered in combination with trospium chloride under the brand name COBENFY. Food intake can influence the absorption of this combination medicine. Taking it with meals may significantly reduce the absorption of trospium chloride, while food may increase the overall exposure to xanomeline. High-fat meals can increase xanomeline exposure by approximately 30% and reduce trospium chloride exposure by approximately 85–90%.

CONTRAINDICATIONS

Xanomeline in combination with trospium chloride is contraindicated in patients with urinary retention, gastric retention, untreated narrow-angle glaucoma and known hypersensitivity to the drug or its ingredients. It should also be avoided in patients with moderate or severe hepatic impairment. Caution is required in patients with kidney disorders, gastrointestinal obstruction and cardiovascular conditions. Proper medical evaluation is necessary before starting treatment to prevent complications and ensure safe use of the medication.

SIDE EFFECTS

• Nausea

• Vomiting

• Constipation

• Diarrhea

• Abdominal pain

• Indigestion

• Heartburn

• Increased heart rate (tachycardia)

• High blood pressure

• Dizziness

• Dry mouth

• Blurred vision

Over Dose

Overdose of xanomeline in combination with trospium chloride (COBENFY) may cause excessive cholinergic or anticholinergic effects in the body. Symptoms may include seizures, vomiting, diarrhoea, abdominal pain, excessive sweating, increased salivation, confusion, agitation, dizziness, rapid heartbeat, high blood pressure, blurred vision, dry mouth and urinary retention. In severe cases, overdose may lead to serious neurological and cardiovascular complications. Immediate medical attention is required. Management includes supportive treatment, close monitoring of vital signs and appropriate medical management of symptoms.

TOXICITY

Xanomeline toxicity, particularly when used in combination with trospium chloride (COBENFY), may occur due to excessive cholinergic and anticholinergic activity in the body. It can affect the gastrointestinal, cardiovascular and central nervous systems. Toxic symptoms may include excessive sweating, increased salivation, nausea, vomiting, diarrhoea, abdominal pain, dizziness, rapid heartbeat, increased blood pressure, dry mouth, blurred vision, confusion and agitation. In severe cases, seizures, low blood pressure, intestinal obstruction and urinary retention may occur. Elderly patients may be more susceptible to anticholinergic effects. Management involves immediate medical attention, supportive treatment, monitoring of vital signs and appropriate treatment of symptoms under medical supervision.