Cobenfy (xanomeline and trospium chloride) is a new treatment for schizophrenia used to improve positive and negative symptoms. Cobenfy contains xanomeline, which helps schizophrenia symptoms, and trospium, which works to reduce the side effects. Cobenfy is a new class of medicine and works differently than traditional schizophrenia medications so it does not have a boxed warning and atypical antipsychotic class warnings and precautions.

Schizophrenia is related to imbalances in messenger systems in the brain involving muscarinic acetylcholine and dopamine. It is thought that Cobenfy works by xanomeline activating muscarinic receptors  (M1 and M4) in the brain (central nervous system), which improves schizophrenia. Trospium chloride cannot enter the brain easily, so it works mainly around the body, reducing side effects by blocking muscarinic receptors.

Cobenfy has two mechanisms of action (MOA). Cobenfy’s active ingredient xanomeline’s MOA is a muscarinic agonist that selectively targets M1 and M4 receptors in the brain without blocking D2 receptors. Cobenfy’s active ingredient trospium chloride’s MOA is a muscarinic antagonist that blocks the muscarinic receptors primarily in the peripheral tissues.

Cobenfy FDA approval is for the treatment of schizophrenia in adults. Cobenfy capsules are taken twice daily on an empty stomach, at least 1 hour before a meal or at least 2 hours after a meal. During drug development, it was named KarXT, and once approved, Bristol Myers Squibb renamed it Cobenfy.

What is the schizophrenia?

Schizophrenia is a mental illness that affects how you think, feel, and behave. Signs and symptoms usually appear first in the teenage years or early adulthood. There are three main areas of symptoms areas, which are positive (hallucinations and delusions), negative (social withdrawal, lack of enjoyment in life), and cognitive impairment (problems with concentration, memory, and decision-making).
Tradition schizophrenia medicines mainly target positive symptoms, whereas Cobenfy helps to improve positive and negative symptoms.

Cobenfy side effects 

Common Cobenfy side effects

The most common Cobenfy side effects were:

• feeling sick (nausea),
• indigestion (dyspepsia),
• constipation,
• vomiting,
• high blood pressure (hypertension),
• abdominal pain,
• diarrhea,
• fast heart rate (tachycardia),
• dizziness,
• and heartburn (gastrointestinal reflux disease).

These side effects occurred in 5% or more of patients, and at least twice the placebo rates in clinical trials.

Serious Cobenfy side effects

Urinary Retention: Cobenfy cause the side effect of urinary retention. Patients may be at increased risk of urinary retention if they are geriatric patients, patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), or diabetic cytopathic patients). It should not be used in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment.

Patients with Hepatic Impairment: Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of Cobenfy, compared to patients with normal hepatic function, which may result in an increased incidence of adverse reactions.

It should not be used in patients with moderate or severe hepatic impairment and is not recommended in patients with mild hepatic impairment. Assess liver enzymes before starting treatment and as clinically indicated during treatment.

Biliary Disease: In clinical studies with Cobenfy, side effects included transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.

It is not recommended for patients with active biliary disease, such as symptomatic gallstones. Assess liver enzymes and bilirubin before starting treatment and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated.

Cobenfy should be stopped in the presence of signs or symptoms of substantial liver injury, such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values.

Decreased Gastrointestinal Motility: Cobenfy contains trospium chloride which like other antimuscarinic agents, may decrease gastrointestinal motility. Use this medicine with caution in patients with gastrointestinal obstructive disorders due to the risk of gastric retention. Use these capsules with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.

Risk of Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with Cobenfy and trospium chloride, an ingredient of Cobenfy. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue medicine and initiate appropriate therapy and/or measures necessary to ensure a patent airway. This medicine is contraindicated in patients with a history of hypersensitivity to trospium chloride.

Patients with Narrow-angle Glaucoma: Pupillary dilation may occur due to the anticholinergic effects of this medicine. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, Cobenfy should only be used if the potential benefits outweigh the risks and with careful monitoring.

Increases in Heart Rate: Cobenfy can increase heart rate so assess heart rate at baseline and as clinically indicated during treatment with this medicine.

Anticholinergic Adverse Reactions in Patients with Renal Impairment: Trospium chloride, an active ingredient in this medicine, is substantially excreted by the kidney. It is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment.

Central Nervous System Effects: Trospium chloride, an active ingredient in this medicine is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Patients should not to drive or operate heavy machinery until they know how this medicine affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.

This is not a complete list of side effects, and others may occur. Call your doctor for medical advice about side effects.

Who should not take this medicine?

Cobenfy should not be taken if you have:

• urinary retention 
• moderate or severe hepatic impairment 
• gastric retention  
• history of hypersensitivity to Cobenfy or trospium chloride (4) 
• untreated narrow-angle glaucoma 

Before taking this medicine

Before taking this Cobenfy, tell your healthcare provider about all of your medical conditions, including if you: 

• have an enlarged prostate, problems passing urine, or a blockage in your urinary bladder 
• have liver problems 
• have or had gallstones or problems with your bile ducts or pancreas 
• have stomach or intestinal problems including constipation, ulcerative colitis, slow emptying of your stomach, or myasthenia gravis 
• have an eye condition called narrow-angle glaucoma 
• have kidney problems 

Pregnancy

Tell your healthcare provider if you are pregnant or plan to become pregnant, as it is not known if this Cobenfy may harm your unborn baby. If you become pregnant or think you are pregnant during treatment with this medicine, tell your healthcare provider. There is a pregnancy exposure registry for women who take this medicine during pregnancy. The purpose of this registry is to collect information about the health of women exposed to Cobenfy and their baby. If you become pregnant during treatment while taking this medicine, your healthcare provider will register you by calling 1-866-961-2388. 

Breastfeeding

Tell your healthcare provider if you are breastfeeding or plan to breastfeed. It is not known if Cobenfy passes into your breast milk or if it can harm your baby.

How should I take Cobenfy?

• Take capsule 2 times each day at least 1 hour before a meal or at least 2 hours after a meal. 
• Do not open the capsules. 
• Take this medicine exactly as your healthcare provider tells you. Do not change the dose or stop taking this medicine without first talking to your healthcare provider. 

Cobenfy Dosing Information

Recommended starting Cobenfy dosage

•  50mg/20mg orally twice daily for at least two days, then increase the dosage to 100mg/20mg twice daily for at least five days.
• Dosage may be increased to 125 mg/30 mg orally twice daily based on patient tolerability and response. 
• See the full prescribing information for the recommended titration and maximum recommended dosage.

Geriatric patients: Recommended starting dosage is 50 mg/20mg orally twice daily. Consider a slower titration. The maximum recommended dosage is 100mg/20mg twice daily. (2.3)

General dosing information

• Take at least 1 hour before a meal or at least 2 hours after a meal. 
• Do not open capsules. (2.2) 
• Assess liver enzymes and bilirubin before starting treatment with this medicine and as clinically indicated during treatment. 
• Assess heart rate at baseline and as clinically indicated during treatment with Cobenfy.

Cobenfy capsules are available in strengths: 50mg/20mg, 100mg/20mg, 125mg/30mg (xanomeline/trospium chloride)

What happens if I overdose?

If you take too much Cobenfy call your healthcare provider or Poison Help Line at 1-800-222-1222, or go to the nearest hospital emergency room right away.

Interactions

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Cobenfy and other medicines may affect each other, causing side effects. Know the medicines you take and keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

Medications that interact with Cobenfy include:

Drugs Eliminated by Active Tubular Secretion: Monitor for increased frequency and/ or severity of adverse reactions related to Cobenfy and to drugs eliminated by active tubular secretion. 

Strong CYP2D6 Inhibitors: Monitor for increased frequency and/or severity of Cobenfy related adverse reactions.

Sensitive Substrates of CYP3A4 or P-glycoprotein: Monitor for increased frequency and/ or severity of adverse reactions from these substrates. 

Antimuscarinic Drugs: Monitor for increased frequency or severity of anticholinergic adverse reactions.

Not all possible interactions are listed here. Other drugs may interact with Cobenfy, including prescription and over-the-counter medicines, vitamins, and herbal products. 

Storage

Store at room temperature between 68°F to 77°F (20°C to 25°C)

Cobenfy ingredients 

Active ingredients:  xanomeline and trospium chloride 

Inactive ingredients: ascorbic acid, lactose monohydrate, microcrystalline cellulose, and talc Capsule shell: contains black iron oxide (only100mg/20mg), hypromellose, red iron oxide, titanium dioxide, and yellow iron oxide (only 50mg/20mg and 100mg/20mg)

Clozapine is an antipsychotic medicine. It works by changing the actions of chemicals in the brain.

Clozapine is used to treat schizophrenia in adults after other treatments have failed.

Clozapine is also used to reduce the risk of suicidal behavior in adults with schizophrenia or similar disorders.

Warnings

Clozapine affects your immune system. You may get infections more easily, even serious or fatal infections. Call your doctor if you have a fever, sore throat, weakness, or lack of energy.

Clozapine can increase your risk of seizure, especially at high doses. Avoid any activity that could be dangerous if you have a seizure or lose consciousness.

Clozapine can cause serious heart problems. Call your doctor right away if you have chest pain, trouble breathing, fast or pounding heartbeats or sudden dizziness.

Clozapine is not approved for use in older adults with dementia-related psychosis.

Before taking this medicine

Clozapine may increase the risk of death in older adults with dementia-related psychosis and is not approved for this use.

You should not take clozapine if you are allergic to it.

To make sure this medicine is safe for you, tell your doctor if you have ever had:

• heart problems, high blood pressure,
• a heart attack or stroke (including “mini-stroke”);
• long QT syndrome (in you or a family member);
• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood);
• a seizure, head injury, or brain tumor;
• diabetes, or risk factors such as being overweight or having a family history of diabetes;
• high cholesterol or triglycerides;
• constipation or problems with your bowel movements;
• liver or kidney disease;
• an enlarged prostate or urination problems;
• glaucoma;
• malnourishment or dehydration; or
• if you smoke.

Taking antipsychotic medicine in the last 3 months of pregnancy may cause breathing problems, feeding problems, or withdrawal symptoms in the newborn. However, you may have withdrawal symptoms or other problems if you stop taking your medicine during pregnancy. If you get pregnant, tell your doctor right away. Do not stop taking clozapine without your doctor’s advice.

You should not breastfeed while using this medicine.

Clozapine is not approved for use by anyone younger than 18 years old.

How should I take clozapine?

Take clozapine exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose.

You may take clozapine with or without food.

Shake the oral suspension (liquid) for 10 seconds before you measure a dose. Use the dosing syringe provided, or use a medicine dose-measuring device (not a kitchen spoon).

Remove an orally disintegrating tablet from the package only when you are ready to take the medicine. Place the tablet in your mouth and allow it to dissolve, without chewing. Swallow several times as the tablet dissolves.

Clozapine affects your immune system and can have long lasting effects on your body. You may get infections more easily, even serious or fatal infections. You may need frequent medical tests while using this medicine and for a short time after your last dose.

You should not stop using clozapine suddenly. Follow your doctor’s instructions about tapering your dose.

If you start taking clozapine again after 2 or more days off the medicine, you may need to use a lower dose than when you stopped. Follow your doctor’s dosing instructions very carefully.

Your doctor may recommend you use a laxative while taking clozapine. Use only the type of laxative your doctor recommends.

Store at room temperature away from moisture and heat.

Dosing information

Usual Adult Dose for Schizophrenia:

Initial dose: 12.5 mg orally once or twice a day
Titration and Maintenance dose: May increase total daily dose in increments of 25 mg to 50 mg per day to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of week 2. Subsequent dose increases can be in increments of up to 100 mg once or twice weekly.
Maximum dose: 900 mg per day

Comments:
-The absolute neutrophil count (ANC) must be 1500/microL or greater for the general population and at least 1000/microL for patients with documented Benign Ethnic Neutropenia (BEN) prior to initiating treatment; to continue therapy, the ANC must be monitored regularly.
-A low starting dose, gradual titration, and divided doses are necessary to minimize the risk of orthostatic hypotension, bradycardia, and syncope.
-When therapy is interrupted for 2 or more days, re-initiate with 12.5 mg once or twice a day; based on tolerability, a dose that is restarted may be increased to a previously therapeutic dose more quickly than it was for initial treatment.

Uses:
-For the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment
-To reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder, who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

If you miss taking clozapine for more than 2 days in a row, call your doctor before you start taking it again.

Get your prescription refilled before you run out of medicine completely.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line .

Overdose symptoms may include drowsiness, confusion, fast heartbeats, feeling light-headed, weak or shallow breathing, drooling, choking, or seizure.

What to avoid

Do not drink alcohol. Dangerous side effects or death could occur.

Avoid coffee, tea, cola, energy drinks or other sources of caffeine.

Avoid driving or hazardous activity until you know how clozapine will affect you. Dizziness or drowsiness can cause falls, accidents, or severe injuries.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.

Clozapine side effects

Get emergency medical help if you have signs of an allergic reaction to clozapine (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

You may get infections more easily, even serious or fatal infections. Call your doctor right away if you have signs of infection such as:

• fever, flu-like symptoms, extreme weakness;
• mouth sores, skin sores;
• new or worsening cough, trouble breathing;
• pain or burning when you urinate; or
• vaginal itching or discharge.

Further doses may be delayed until your infection clears up.

High doses or long-term use of clozapine can cause a serious movement disorder that may not be reversible. The longer you use clozapine, the more likely you are to develop this disorder, especially if you are a woman or an older adult.

Clozapine can increase your risk of seizure, especially at high doses. Avoid any activity that could be dangerous if you have a seizure or lose consciousness.

Call your doctor at once if you have:

• uncontrolled muscle movements in your face (chewing, lip smacking, frowning, tongue movement, blinking or eye movement);
• a seizure (blackout or convulsions);
• severe constipation;
• dry or hard bowel movements, or painful gas;
• nausea, vomiting, stomach pain or bloating;
• heart problems – chest pain, fast or pounding heartbeats, fluttering in your chest, slow heartbeats, shortness of breath, and sudden dizziness (like you might pass out);
• liver problems – loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
• severe nervous system reaction – very stiff (rigid) muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, feeling like you might pass out; or
• signs of a blood clot in the lung – chest pain, sudden cough, wheezing, rapid breathing, coughing up blood.

Untreated constipation may lead to serious bowel complications, hospitalization, or death. Tell your doctor right away if you are not having bowel movements at least 3 times per week.

Common clozapine side effects may include:

• weight gain;
• dizziness, tremor;
• fast heart rate;
• headache, drowsiness;
• nausea, constipation;
• dry mouth, or increased salivation;
• vision problems; or
• fever, increased sweating.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

What other drugs will affect clozapine?

When you start or stop taking clozapine, your doctor may need to adjust the doses of any other medicines you take on a regular basis.

Clozapine can cause a serious heart problem. Your risk may be higher if you also use certain other medicines for infections, asthma, heart problems, high blood pressure, depression, mental illness, cancer, malaria, or HIV.

Using clozapine with other drugs that make you drowsy or slow your breathing can cause dangerous side effects or death. Ask your doctor before using opioid medication, a sleeping pill, a muscle relaxer, cold or allergy medicine, or medicine for anxiety or seizures.

Many drugs can affect clozapine. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any medicine you start or stop using.