AUDIENCE: Psychiatry, Pharmacy, Hematology
ISSUE: FDA is making changes to the requirements for monitoring, prescribing, dispensing, and receiving the schizophrenia medicine clozapine, to address continuing safety concerns and current knowledge about a serious blood condition called severe neutropenia. Severe neutropenia is a dangerously low number of neutrophils, white blood cells that help fight infections. Severe neutropenia can be life-threatening.
There are two parts to the changes in the requirements for treating patients with clozapine. First, FDA clarified and enhanced the prescribing information for clozapine that explains how to monitor patients for neutropenia and manage clozapine treatment. Second, FDA approved a new, shared risk evaluation and mitigation strategy (REMS) called the Clozapine REMS Program. The revised prescribing information and the Clozapine REMS Program will improve monitoring and management of patients with severe neutropenia. The shared REMS is also expected to reduce the burden and possible confusion related to having separate registries for individual clozapine medicines. The requirements to monitor, prescribe, dispense, and receive all clozapine medicines are now incorporated into the Clozapine REMS Program.
BACKGROUND: Clozapine is an antipsychotic medicine used to treat schizophrenia in patients whose symptoms are not controlled with standard antipsychotic treatment. It is also used to treat recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
RECOMMENDATION: Patients who are currently treated with clozapine will be automatically transferred to the Clozapine REMS Program. In order to prescribe and dispense clozapine, prescribers and pharmacies will be required to be certified in the Clozapine REMS Program according to a specific transition schedule starting October 12, 2015 (see Additional Information for Prescribers, Additional Information for Pharmacies, and Additional Information for Patients and Caregivers sections of the Drug Safety Communication at: http://www.fda.gov/Drugs/DrugSafety/ucm461853.htm for more details).
For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.
Clozapine can cause a serious blood condition. Your doctor will order certain lab tests before you start your treatment, during your treatment, and for at least 4 weeks after your treatment. Your doctor will order the lab tests once a week at first and may order the tests less often as your treatment continues. If you experience any of the following symptoms, call your doctor immediately: extreme tiredness; weakness; fever, sore throat, chills, or other signs of flu or infection; or sores in your mouth or throat.
A program has been set up by the manufacturers of clozapine to be sure that people do not take clozapine without the necessary monitoring. You, your doctor, and your pharmacist must be registered with the program, and your pharmacist will not dispense your medication unless he or she has received the results of your blood tests. Ask your doctor for more information about this program and how you will receive your medication.
Clozapine may cause seizures. Tell your doctor if you have or have ever had seizures. Do not drive a car, operate machinery, swim, or climb while taking clozapine, because if you suddenly lose consciousness, you could harm yourself or others.
Clozapine may cause myocarditis (swelling of the heart muscle that may be dangerous). If you experience any of the following symptoms, call your doctor immediately: extreme tiredness; difficulty breathing or fast breathing; fever; chest pain; or fast, irregular, or pounding heartbeat.
Clozapine may cause dizziness, lightheadedness, or fainting when you stand up, especially when you first start taking it or when your dose is increased. Tell your doctor if you are taking medications for anxiety such as diazepam (Valium), sleeping pills, or other medications for schizophrenia. Your doctor will probably start you on a low dose of clozapine and gradually increase your dose to give your body time to adjust to the medication and decrease the chance that you will experience this side effect. Talk to your doctor if you do not take clozapine for 2 days or longer. Your doctor will probably tell you to restart your treatment with a low dose of clozapine.
Use in Older Adults:
Studies have shown that older adults with dementia (a brain disorder that affects the ability to remember, think clearly, communicate, and perform daily activities and that may cause changes in mood and personality) who take antipsychotics (medications for mental illness) such as clozapine have an increased chance of death during treatment.
Clozapine is not approved by the Food and Drug Administration (FDA) for the treatment of behavior problems in older adults with dementia. Talk to the doctor who prescribed clozapine if you, a family member, or someone you care for has dementia and is taking this medication. For more information visit the FDA website: http://www.fda.gov/Drugs
Why is this medication prescribed?
Clozapine is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) in patients who have not been helped by other medications or who have tried to kill themselves and are likely to try to kill or harm themselves again. Clozapine is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.
How should this medicine be used?
Clozapine comes as a tablet and an orally disintegrating tablet (tablet that dissolves quickly in the mouth) to take by mouth. It is usually taken one to three times a day. Take clozapine at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take clozapine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Do not try to push the orally disintegrating tablet through the foil packaging. Instead, use dry hands to peel back the foil. Immediately take out the tablet and place it on your tongue. The tablet will quickly dissolve and can be swallowed with saliva. No water is needed to swallow disintegrating tablets.
Clozapine controls schizophrenia but does not cure it. It may take several weeks or longer before you feel the full benefit of clozapine. Continue to take clozapine even if you feel well. Do not stop taking clozapine without talking to your doctor. Your doctor will probably want to decrease your dose gradually.
Other uses for this medicine
This medication should not be prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions should I follow?
Before taking clozapine,
- tell your doctor and pharmacist if you are allergic to clozapine or any other medications.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention those listed in the IMPORTANT WARNING section and any of the following: antihistamines; benztropine (Cogentin); cimetidine (Tagamet); ciprofloxacin (Cipro); dicyclomine (Bentyl); epinephrine; erythromycin (E.E.S., E-Mycin, others); medications for high blood pressure, mental illness, or nausea; medications for irregular heartbeat such as encainide, flecainide (Tambocor), propafenone (Rythmol), and quinidine (Quinidex);medications for seizures such as carbamazepine (Tegretol) or phenytoin (Dilantin); rifampin (Rifadin, Rimactane); sedatives; selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft);sleeping pills; tranquilizers; and trihexyphenidyl (Artane). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- in addition to the condition listed in the IMPORTANT WARNING section, tell your doctor if you have or have ever had problems with your urinary system or prostate (a male reproductive gland); paralytic ileus (condition in which food cannot move through the intestine); glaucoma; irregular heartbeat; high or low blood pressure; or heart, kidney, lung, or liver disease; or if you or anyone in your family has or has ever had diabetes. Also tell your doctor if you have ever had to stop taking a medication for mental illness because of severe side effects.
- tell your doctor if you are pregnant, especially if you are in the last few months of your pregnancy, or if you plan to become pregnant or are breast-feeding. If you become pregnant while taking clozapine, call your doctor. Clozapine may cause problems in newborns following delivery if it is taken during the last months of pregnancy.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking clozapine.
- you should know that alcohol can add to the drowsiness caused by this medication.
- tell your doctor if you use tobacco products. Cigarette smoking may decrease the effectiveness of this medication.
- you should know that you may experience hyperglycemia (increases in your blood sugar) while you are taking this medication, even if you do not already have diabetes. If you have schizophrenia, you are more likely to develop diabetes than people who do not have schizophrenia, and taking clozapine or similar medications may increase this risk. Tell your doctor immediately if you have any of the following symptoms while you are taking clozapine: extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness. It is very important to call your doctor as soon as you have any of these symptoms, because high blood sugar can cause a serious condition called ketoacidosis. Ketoacidosis may become life-threatening if it is not treated at an early stage. Symptoms of ketoacidosis include: dry mouth, nausea and vomiting, shortness of breath, breath that smells fruity, and decreased consciousness.
- if you have phenylketonuria (PKU, an inherited condition in which a special diet must be followed to prevent mental retardation), you should know that the orally disintegrating tablets contain aspartame that forms phenylalanine.
What special dietary instructions should I follow?
Talk to your doctor about drinking caffeinated beverages while taking this medicine.
What should I do if I forget a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
If you miss taking clozapine for more than 2 days, you should call your doctor before taking any more medication. Your doctor may want to restart your medication at a lower dose.
What side effects can this medication cause?
Clozapine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- increased salivation
- dry mouth
Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNINGS or SPECIAL PRECAUTIONS sections, call your doctor immediately:
- shaking hands that you cannot control
- difficulty urinating or loss of bladder control
- changes in vision
- severe muscle stiffness
- changes in behavior
- sore throat
- unusual bleeding or bruising
- loss of appetite
- upset stomach
- yellowing of the skin or eyes
- pain in the upper right part of the stomach
- flu-like symptoms
- lack of energy
Clozapine may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.
If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).
What should I know about storage and disposal of this medication?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed and any orally disintegrating tablets that you removed from the blister pack but did not use immediately. Talk to your pharmacist about the proper disposal of your medication.
In case of emergency/overdose
In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.
Symptoms of overdose may include:
- slow breathing
- change in heartbeat
- loss of consciousness
What other information should I know?
Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to clozapine.
Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.