AUDIENCE: Health Professional, Patient, Pharmacy
ISSUE: The FDA is warning that the medicine lamotrigine (Lamictal) for seizures and bipolar disorder can cause a rare but very serious reaction that excessively activates the body's infection-fighting immune system. This can cause severe inflammation throughout the body and lead to hospitalization and death, especially if the reaction is not diagnosed and treated quickly. As a result, we are requiring a new warning about this risk be added to the prescribing information in the lamotrigine drug labels.
BACKGROUND: The immune system reaction, called hemophagocytic lymphohistiocytosis (HLH), causes an uncontrolled response by the immune system. HLH typically presents as a persistent fever, usually greater than 101°F, and it can lead to severe problems with blood cells and organs throughout the body such as the liver, kidneys, and lungs.
Lamotrigine is used alone or with other medicines to treat seizures in patients two years and older. It may also be used as maintenance treatment in patients with bipolar disorder to help delay the occurrence of mood episodes such as depression, mania, or hypomania. Stopping lamotrigine without first talking to a prescriber can lead to uncontrolled seizures, or new or worsening mental health problems. Lamotrigine has been approved and on the market for 24 years, and is available under the brand name Lamictal and as generics.
RECOMMENDATION: Healthcare professionals should be aware that prompt recognition and early treatment is important for improving HLH outcomes and decreasing mortality. Diagnosis is often complicated because early signs and symptoms such as fever and rash are not specific. HLH may also be confused with other serious immune-related adverse reactions such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
Evaluate patients who develop fever or rash promptly, and discontinue lamotrigine if HLH or another serious immune-related adverse reaction is suspected and an alternative etiology for the signs and symptoms cannot be established. Advise patients to seek immediate medical attention if they experience symptoms of HLH during lamotrigine treatment. A diagnosis of HLH can be established if a patient has at least five of the following eight signs or symptoms:
- fever and rash
- enlarged spleen
- elevated levels of triglycerides or low blood levels of fibrinogen
- high levels of blood ferritin
- hemophagocytosis identified through bone marrow, spleen, or lymph node biopsy
- decreased or absent Natural Killer (NK) Cell activity
- elevated blood levels of CD25 showing prolonged immune cell activation
Patients or their caregivers should contact their health care professionals right away if they experience any symptom of HLH while taking lamotrigine. HLH can occur within days to weeks after starting treatment. A physical examination and specific laboratory blood tests and other evaluations are used to diagnose HLH. Signs and symptoms of HLH include but are not limited to:
- enlarged liver; symptoms may include pain, tenderness, or unusual swelling over the liver area in the upper right belly
- swollen lymph nodes
- skin rashes
- yellow skin or eyes
- unusual bleeding
- nervous system problems, including seizures, trouble walking, difficulty seeing, or other visual disturbances
Read the patient Medication Guide, which explains the benefits and risks of lamotrigine, every time you get a new prescription because the information may change. Do not stop taking lamotrigine without talking to your health care professional first as doing so can cause serious problems.
For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.
Lamotrigine may cause rashes, including serious rashes that may need to be treated in a hospital or cause permanent disability or death. Tell your doctor if you are taking valproic acid (Depakene) or divalproex (Depakote) because taking these medications with lamotrigine may increase your risk of developing a serious rash. Also tell your doctor if you have ever developed a rash after taking lamotrigine or any other medication for epilepsy or if you are allergic to any medications for epilepsy.
Your doctor will start you on low dose of lamotrigine and gradually increase your dose, not more than once every 1 to 2 weeks. You may be more likely to develop a serious rash if you take a higher starting dose or increase your dose faster than your doctor tells you that you should. Your first doses of medication may be packaged in a starter kit that will clearly show you the right amount of medication to take each day during the first 5 weeks of your treatment. This will help you to follow your doctor's instructions as your dose is slowly increased. Be sure to take lamotrigine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.
Serious rashes usually develop during the first 2 to 8 weeks of treatment with lamotrigine, but can develop at any time during treatment. If you develop any of the following symptoms while you are taking lamotrigine, call your doctor immediately: rash; blistering or peeling of the skin; hives; fever; swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs; hoarseness; difficulty breathing or swallowing; nausea; extreme tiredness; unusual bruising or bleeding; lack of energy; loss of appetite; pain in the upper right part of the stomach; yellowing of the skin or eyes; flu-like symptoms; pale skin; headache; dizziness; fast heartbeat; weakness; shortness of breath; sore throat, fever, chills, and other signs of infection; dark red or cola-colored urine; muscle weakness or aching; or painful sores in your mouth or around your eyes.
Talk to your doctor about the risks of taking lamotrigine or of giving lamotrigine to your child. Children 2-17 years of age who take lamotrigine are more likely to develop serious rashes than adults who take the medication.
Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with lamotrigine and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer's website to obtain the Medication Guide.
Why is this medication prescribed?
Lamotrigine extended-release (long-acting) tablets are used with other medications to treat certain types of seizures in patients who have epilepsy. All types of lamotrigine tablets (tablets, orally disintegrating tablets, and chewable tablets) other than the extended-release tablets are used alone or with other medications to treat seizures in people who have epilepsy or Lennox-Gastaut syndrome (a disorder that causes seizures and often causes developmental delays). All types of lamotrigine tablets other than the extended-release tablets are also used to increase the time between episodes of depression, mania (frenzied or abnormally excited mood), and other abnormal moods in patients with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Lamotrigine has not been shown to be effective when people experience the actual episodes of depression or mania, so other medications must be used to help people recover from these episodes. Lamotrigine is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.
How should this medicine be used?
Lamotrigine comes as a tablet, an extended-release tablet, an orally disintegrating tablet (dissolves in the mouth and can be swallowed without water), and a chewable dispersible (can be chewed or dissolved in liquid) tablet to take by mouth with or without food. The extended-release tablets are taken once a day. The tablets, orally disintegrating tablets, and chewable dispersible tablets are usually taken once or twice a day, but may be taken once every other day at the beginning of treatment. Follow the directions on your prescription label carefully and ask your doctor or pharmacist to explain any part you do not understand.
There are other medications that have names similar to the brand name for lamotrigine. You should be sure that you receive lamotrigine and not one of the similar medications each time you fill your prescription. Be sure that the prescription your doctor gives you is clear and easy to read. Talk to your pharmacist to be sure that you are given lamotrigine. After you receive your medication, compare the tablets to the pictures in the manufacturer's patient information sheet. If you think you were given the wrong medication, talk to your pharmacist. Do not take any medication unless you are certain it is the medication that your doctor prescribed.
Swallow the tablets and extended-release tablets whole; do not split, chew, or crush them.
If you are taking the chewable dispersible tablets, you may swallow them whole, chew them, or dissolve them in liquid. If you chew the tablets, drink a small amount of water or diluted fruit juice afterward to wash down the medication. To dissolve the tablets in liquid, place 1 teaspoon (5 mL) of water or diluted fruit juice in a glass. Place the tablet in the liquid and wait 1 minute to allow it to dissolve. Then swirl the liquid and drink all of it immediately. Do not try to divide a single tablet to be used for more than one dose.
To take an orally disintegrating tablet, place it on your tongue and move it around in your mouth. Wait a short time for the tablet to dissolve, and then swallow it with or without water.
If your medication comes in a blisterpack, check the blisterpack before you take your first dose. Do not use any of the medication from the pack if any of the blisters are torn, broken, or do not contain tablets.
If you were taking another medication to treat seizures and are switching to lamotrigine, your doctor will gradually decrease your dose of the other medication and gradually increase your dose of lamotrigine. Follow these directions carefully and ask your doctor or pharmacist if you have questions about how much of each medication you should take.
Lamotrigine may control your condition, but it will not cure it. It may take several weeks for you to feel the full benefit of lamotrigine. Continue to take lamotrigine even if you feel well. Do not stop taking lamotrigine without talking to your doctor, even if you experience side effects such as unusual changes in behavior or mood. Your doctor will probably decrease your dose gradually. If you suddenly stop taking lamotrigine, you may experience seizures. If you do stop taking lamotrigine for any reason, do not start taking it again without talking to your doctor.
Other uses for this medicine
This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions should I follow?
Before taking lamotrigine,
- tell your doctor and pharmacist if you are allergic to lamotrigine, any other medications. or any of the ingredients in the type of lamotrigine tablets you will be taking. Ask your doctor or pharmacist or check the Medication Guide for a list of the ingredients.
- 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 the medications listed in the IMPORTANT WARNING section and methotrexate (Rheumatrex, Trexall); other medications for seizures such as carbamazepine (Tegretol), oxcarbazepine (Trileptal), phenobarbital (Luminal, Solfoton), phenytoin (Dilantin), and primidone (Mysoline); pyrimethamine (Daraprim); rifampin (Rifadin, Rimactane); and trimethoprim (Proloprim). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you are using female hormonal medications such as hormonal contraceptives (birth control pills, patches, rings, injections, implants, or intrauterine devices), or hormone replacement therapy (HRT). Talk to your doctor before you start or stop taking any of these medications while you are taking lamotrigine. If you are taking a female hormonal medication, tell your doctor if you have any bleeding between expected menstrual periods.
- tell your doctor if you have or have ever had an autoimmune disease (condition in which the body attacks its own organs, causing swelling and loss of function) such as lupus (condition in which the body attacks many different organs causing a variety of symptoms), a blood disorder, or kidney or liver disease.
- tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking lamotrigine, call your doctor.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking lamotrigine.
- you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
- remember that alcohol can add to the drowsiness caused by this medication.
- you should know that your mental health may change in unexpected ways and you may become suicidal (thinking about harming or killing yourself or planning or trying to do so) while you are taking lamotrigine for the treatment of epilepsy, mental illness, or other conditions. A small number of adults and children 5 years of age and older (about 1 in 500 people) who took anticonvulsants such as lamotrigine to treat various conditions during clinical studies became suicidal during their treatment. Some of these people developed suicidal thoughts and behavior as early as one week after they started taking the medication. There is a risk that you may experience changes in your mental health if you take an anticonvulsant medication such as lamotrigine, but there may also be a risk that you will experience changes in your mental health if your condition is not treated. You and your doctor will decide whether the risks of taking an anticonvulsant medication are greater than the risks of not taking the medication. You, your family, or your caregiver should call your doctor right away if you experience any of the following symptoms: panic attacks; agitation or restlessness; new or worsening irritability, anxiety, or depression; acting on dangerous impulses; difficulty falling or staying asleep; aggressive, angry, or violent behavior; mania (frenzied, abnormally excited mood); talking or thinking about wanting to hurt yourself or end your life; withdrawing from friends and family; preoccupation with death and dying; giving away prized possessions; or any other unusual changes in behavior or mood. Be sure that your family or caregiver knows which symptoms may be serious so they can call the doctor if you are unable to seek treatment on your own.
What special dietary instructions should I follow?
Unless your doctor tells you otherwise, continue your normal diet.
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.
What side effects can this medication cause?
Lamotrigine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- loss of balance or coordination
- double vision
- blurred vision
- uncontrollable movements of the eyes
- difficulty thinking or concentrating
- difficulty speaking
- loss of appetite
- weight loss
- stomach, back, or joint pain
- missed or painful menstrual periods
- swelling, itching, or irritation of the vagina
- uncontrollable shaking of a part of the body
Some side effects can be serious. If you experience any of the following symptoms or those described in the IMPORTANT WARNING section, call your doctor immediately:
- seizures that happen more often, last longer, or are different than the seizures you had in the past
- chest pain
- swelling of the hands, feet, ankles, or lower legs
- stiff neck
- sensitivity to light
- loss of consciousness
Lamotrigine may cause other side effects. Call your doctor if you have any unusual problems while you are 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, away from excess heat and moisture (not in the bathroom).
It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org
Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.
In case of emergency/overdose
In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can't be awakened, immediately call emergency services at 911.
Symptoms of overdose may include:
- loss of balance or coordination
- uncontrollable movements of the eyes
- increased seizures
- loss of consciousness
What other information should I know?
Keep all appointments with your doctor and the laboratory. Your doctor may order certain lab tests to check your response to lamotrigine.
Before having any laboratory test, tell your doctor and the laboratory personnel that you are taking lamotrigine.
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.
- Lamictal® CD
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